Cell Pysiology

Cell Physiology- Cellular structures and processes/ Cellular pathology
In terms of rooms, you can picture the nucleus as the office, with bookshelves containing various books and
manuals. How to do home repair, how to do interior remodeling, how to talk to your neighbors, how to take out
the trash, and so on.
Cellular structure and function
Extending the analogy, each book would be like a gene that contains the exact information - like a blueprint -
needed to build a specific protein.
The cell is the basic unit that makes up every living organism.
Drilling down deeper - the exact letters and words of the books are written in the language of DNA.
It's the smallest form of life that can replicate on its own, but cells in our body differ quite a lot from one
another. Now, as it turns out DNA is actually one long molecule with some parts that code for genes connected together
by other parts that don’t code for genes.
The human body alone has over 200 distinct cell types - from long skinny neurons that can get over 1 meter long
to macrophages that gobble up pathogens to myocytes that contract to let you to flex your muscles. If the DNA molecule in a cell were stretched out, it would be about 2 meters long!
But despite their differences, they share lots of similar features. Fortunately, the DNA is tightly coiled and wound in multiple steps so that it packs down really tight.
So let’s imagine the average cell as a small apartment. First, we want some walls to distinction between what’s First off, it’s coiled around proteins called histones.
“outside” and what’s “inside.” These walls are the cell membrane or plasma membrane, and they’re made out of
a double layer of phospholipid molecules. Zoomed in to that level, the DNA looks like pearls on a string. But then that “necklace” gets folded further and
further, creating an extremely neatly folded and tightly packed form of DNA, called a chromosome.
Phospholipids have a “head” made out of negatively charged phosphate, which is hydrophilic - meaning it likes
water. Now, to make a protein, the DNA of a particular gene has to be transcribed, or copied over into RNA - specifically
messenger RNA or mRNA.
Phospholipids also have a “tail” made out of two fatty acids, which are hydrophobic - meaning, they avoid water.
Special structures inside the cell, called ribosomes, can then use the mRNA copies to produce proteins!
In water, phospholipids form a bilayer - where the hydrophobic tails are oriented inwards, where there is no
water, and the hydrophilic heads oriented outwards, in contact with water molecules. The ribosomes are made by a structure within the nucleus called the nucleolus out of ribosomal RNA or rRNA
and proteins.
So the plasma membrane forms a wall with water on both sides.
They’re like the workshop of our cell apartment, with mini 3D printers, printing up various spare parts or tools
This wall is semipermeable - meaning it allows some things through, like oxygen or carbon dioxide - but doesn’t for the apartment - which is the analogy for protein synthesis.
allow other things through, like glucose and sugars.
The ribosome converts mRNA into a string of amino acids which forms the protein in a process called translation.
Fortunately, we have the “doors” and “windows” on this apartment, and they’re made of special protein
channels that are, essentially, tiny tunnels through the phospholipid bilayer. Ribosomes rely on a triplet code, where every three nucleic acids along a sequence of mRNA correspond to one
of the twenty common amino acids or to a stop codon which tells the ribosome to stop building the protein.
These channels allow water and specific ions like sodium and potassium to come in and out of the cell.
So to help visualize all of this, imagine the ribosome floating around in the cytosol.
Now, like any well built apartment, our cell has a sturdy framework called the cytoskeleton.
Once that ribosome binds to mRNA, it uses the cytoskeleton to help make it’s way over to an organelle called
The cytoskeleton is made out of proteins like microfilaments, microtubules, and intermediate filaments, which the endoplasmic reticulum - or ER for short.
all provide structural stability.
The ribosome attaches to the plasma membrane surface of the endoplasmic reticulum and will start translating
The cytoskeleton is also very dynamic, allowing the cell to change shape by selectively contracting and extending the mRNA into a protein that gets directly injected it into the lumen - or the inside - of the ER.
filaments - which is important in some cell functions, like muscle contraction, cell division, and even cell
movement! The ER supports lots of ribosomes on its surface, each of which is busy translating proteins.
The cytoskeleton also helps structures within the cell move from one area to another. To create enough surface area to do this, the ER is really a continuous stack of flattened phospholipid
membrane.
Now that the apartment is built - let’s fill it in. The cell is filled with intracellular fluid called cytosol, which
contains various ions like sodium and potassium. Sort of like a huge deflated balloon, that’s all crumpled up - low in volume, but with a lot of surface area
available!
In addition, cells have a number of organelles, which are like little rooms within our apartment.
The part of ER that produces protein is called “rough ER”, since the ribosomes resemble tiny little bumps that
And together, the cytosol and the organelles make up the cytoplasm of the cell. make the ER look “rough” under electron microscopy.
Now, the nucleus is a highly specialized organelle, which is home to our genetic material. There’s also a “smooth” type of endoplasmic reticulum, which is involved in making lipids, like cholesterol and
phospholipids, that the cell can use for producing more cell membrane.
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In some cells, like the liver, the smooth ER helps with detoxifying harmful chemicals, so in this case, kind of like
the spa or bathroom in the apartment.
In other cells, like glands, the smooth ER uses cholesterol, to go on to create various steroid hormones.
For this reason, some specialized hormone-producing cells, like the ones found in the testes or the ovaries, have
lots of smooth ER.
Another organelle called the Golgi apparatus takes the proteins, lipids, and hormones that are generated in the
rough ER and smooth ER, and packages them into a vesicle made of a double layer of phospholipids that are
then distributed around the cell.
Think of the Golgi apparatus like the garage of the apartment, where you have all your packed-up boxes, that
you sometimes then move and store in other rooms.
There are transport vesicles, which move within the cell, and secretory vesicles which move molecules out of the
cell, a process known as the exocytosis - like taking the garbage out of the garage.
An example of a vesicle that stays in the cell would be the lysosome, which contain enzymes that can help break
down other molecules, as well as large organelles that may be damaged.
Finally, there are the mitochondria, which are organelles that serve as the power generators, like in the utility
closet of our apartment.
In the cytoplasm, glucose goes through glycolysis - which is a metabolic pathway that cleaves the 6-carbon
glucose into two halves, which are 3-carbon molecules called pyruvate.
From there, the pyruvate enters the mitochondria and goes through the citric acid cycle or Krebs cycle, as well as
the electron transport chain, in order to produce adenosine triphosphate - or ATP.
These processes require O2, so this is termed aerobic respiration.
The byproducts of this set of reactions are CO2 and H2O.
Ultimately, about 32 molecules of energy-rich ATP are made for every single molecule of glucose taken in by the
cell.
Alternatively, if there’s not enough glucose to go around, our cell can try burning fatty acids in the mitochondria
as a source of fuel - in a process called beta oxidation.
Now, as it turns out - mitochondria can only work with “medium sized” fatty acids.
So to make it work, a special organelle called the peroxisome chops long fatty acids down into medium sized
ones.
The process generates dangerous hydrogen peroxide, but the peroxisome has an enzyme called peroxidase,
which safely converts the hydrogen peroxide into water and oxygen.
Summary
OK, quick recap! The phospholipid bilayer forms the cell membrane which are the walls of the cell, and the
internal structure of the cell is made up of a cytoskeleton.
The key organelles include the nucleus, which houses the DNA, the endoplasmic reticulum which generates
proteins, lipids, and steroids, and the mitochondria, which provides the cell with energy using aerobic
respiration, which burns glucose, or beta oxidation, which burns fatty acids.
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Without cholesterol, at high temperatures, the phospholipids separate from one another and that makes the
membrane leaky and weak.
Cell membrane So the role of cholesterol is twofold. At low temperatures, it squeezes in between phospholipid molecules and
keeps them from packing too tightly together to keep the membrane more fluid.
The cell membrane is an important structural element of the building block of life - the cell. And at high temperatures, cholesterol pulls phospholipid molecules together, decreasing the space between
them.
Its main role is to define what's inside - the intracellular space - and what’s outside - the extracellular space.
So cholesterol makes the cell membrane fluid and durable, no matter the weather.
It also regulates what comes in or out of the cell - that’s called selective permeability.
This is particularly important for cells like red blood cells that have cell membranes that see a lot of wear and
The cell membrane is basically made up of a bilayer of phospholipid molecules.
tear over time, and get exposed to different temperatures.
Phospholipids are amphiphilic molecules, meaning “both-loving”.
In fact, that’s why red blood cells have membranes with even higher levels of cholesterol than normal.
Now, the phospholipid is made out of three things - their head, which is made out of negatively charged
Cell membranes have various membrane proteins embedded within them.
phosphate, a tail - made out of two fatty acids, and a skeleton made out of glycerol, that brings everything
together. There are integral proteins, that span the cell membrane bilayer, peripheral proteins, which are found on the
inner or the outer edge of the membrane, and lipid bound proteins, which can be found hanging out in between
Their “head” is hydrophilic - meaning it likes water. Meanwhile, their “tail” is lipophilic - meaning, it loves fats.
the phospholipid layers.
These lipophilic parts also exclude water - so they’re not just lipophilic, they’re also hydrophobic.
Some of these membrane proteins are transport proteins, and they’re examples of integral proteins because
In water, phospholipids form a bilayer - where the hydrophobic tails are oriented inwards, where there are no they span across the membrane.
water molecules, and the hydrophilic heads oriented outwards, in contact with water molecules.
Transport proteins help move molecules that can’t freely diffuse across the membrane, to get in and out of the
So the plasma membrane forms a wall with water on both sides. cell.
The cell membrane is also semipermeable. There are two types of transport proteins: channels and carriers.
That means that the membrane allows some molecules to pass through, but not others - and it’s mostly based Channel proteins open to form a sort of a tunnel through the membrane, through which water and ions can flow
on the molecule’s size, polarity, and charge. right through.
There are roughly five categories. Small and nonpolar molecules, like oxygen or carbon dioxide will diffuse An example would be an aquaporin channel, which opens and closes to let water in.
through the membrane quickly.
In contrast, carriers are very specific - they have special binding sites that only allow certain molecules to bind to
Small, polar molecules, like water, will be able to pass through, but it happens relatively slowly. them, and they also have gates at both ends, which open sequentially.
That’s because even though the middle of the phospholipid bilayer is hydrophobic, the occasional molecule of One example of a carrier protein is the glucose transporter called GLUT4.
water can sort of slip through because it’s such a small molecule.
By default, the transporter is open to the outside, waiting for a glucose molecule to float by.
Now, large and nonpolar molecules, such as retinol - also known as Vitamin A1 - can also cross the cell
When a glucose molecule binds to a special site within the transporter, the outer gate closes, and the inner gate
membrane thanks to them being non-polar - but once again, the crossing is really slow, because the molecule is
opens.
so large.
The glucose then unbinds, and float freely into the cell, while the transporter will reset, awaiting for the next
Now, as you might guess, large, polar molecules, like glucose, are unlikely to pass the cell membrane on their
glucose molecule.
own.
There’s also a special family of transport proteins, which are essentially enzymes.
Highly polar, charged ions like Na+, K+, Cl-, or molecules that possess a charge, like amino acids stand no chance
at passing the cell membrane These transport proteins use the energy from adenosine triphosphate, or ATP, to actively pump various ions in
or out of the cell, against their concentration gradient. That gives them their name - ATPases.
In addition to phospholipid bilayers, membranes also contain cholesterol.
In other words, these ATPases push ions from the side with a low concentration, over to the side with a high
Without cholesterol, at low temperatures, the phospholipids pack tightly together and become less fluid, and
concentration.
that makes the membrane brittle.
An example is the Na+/K+ ATPase, which pumps 3 ions of sodium out of the cell in exchange for 2 ions of
potassium into the cell - both going against their concentration gradient.
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Cell membranes also contain cell adhesion molecules, or CAMs, which are integral transmembrane proteins that Summary
anchor the cell in place by attaching it to other cells.
These cell adhesion molecules come together and create junctions, called adherens junctions or tight junctions. Alright, as a quick recap - the phospholipid bilayer contains cholesterol, which makes it more durable at all
temperatures, as well as various proteins.
An example of a cell adhesion molecules would be the cadherin, a membrane protein whose job is to hold tight
to neighboring cell cadherins, at an adherens junction. Transport proteins help move molecules across the membrane, cell surface receptors receive signals from other
cells, and adhesion proteins, keep the cell anchored to neighboring cells.
Think of them as velcro, attaching the two cells together.
Finally, the cell membrane contains carbohydrates in the form of glycoproteins and glycolipids, which help cells
The tight junction is, well, even tighter, and creates a fully waterproof seal through the creation of protein recognize one another.
complexes, and that sort of resembles rivets joining metal plates together, ensuring waterproofing.
Cell adhesion molecules and junctions are essential for the structural integrity of multicellular tissues, they’re
like the mortar and the cell are like bricks - together forming a strong brick wall.
Next, there are cell surface receptors, which receive an input from the outside and transmit it to the inside of
cell.
The input is usually something that other cells produce, like hormones, cytokines, or growth factors - so cell
surface receptors are sort of like the cells’ mailbox - receiving news from the world.
If a hormone binds to a receptor, the receptor changes its shape, and that triggers a chain of events within the
cell.
For example, when there’s a lot of glucose in the blood, the pancreas secretes insulin, which is a peptide
hormone that binds to insulin receptors on various cells.
Now, this receptor also functions as a tyrosine kinase.
Kinases are enzymes that add phosphate groups so when insulin binds to the insulin receptor, the receptor
autophosphorylates - meaning, it transfers a phosphate group from an ATP molecule onto the receptor. This
triggers a cascade of intracellular events.
The end result is that the cell mobilizes spare GLUT4 transporters, which are mostly chilling inside of the cell on
small bubbles of phospholipid bilayer, called a vesicle.
The vesicle with the transporters then moves to the membrane, and fuses with it, therefore allowing more
GLUT4 transporters to do their job - which speeds up glucose intake.
It’s like the cell is getting a love letter from the pancreas, that says “open the door to get a sweet treat”. How
cool is that?
Aside from cholesterol and proteins, cell membranes also contain various carbohydrates, which are usually
bound to proteins, creating glycoproteins, or bound to lipids - creating glycolipids.
These glycoproteins and glycolipids are unique to each cell and help cells recognize one another - a bit like
identification cards.
In fact, immune cells often distinguish normal cells from invading pathogens based on the glycoproteins and
glycolipids on the cell surface.
Now, the proteins and cholesterol within the bilayer aren’t static - but float horizontally through the
phospholipids.
In fact, if you look at a cell membrane from above it looks a bit like a mosaic with parts that can move around, so
that’s why the cell membrane is sometimes referred to as a fluid mosaic model.
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Finally, there’s osmosis which - in addition to being an awesome company that explains medical topics
really clearly - also describes the movement of water across the cell membrane.
Selective permeability of the cell membrane It’s a special case of facilitated diffusion, because water uses channels called aquaporins to move across the
membrane.
The cell membrane is there to define what's on the inside of a cell - the intracellular space - versus what’s Osmosis is driven by osmotic pressure which is a force determined by the difference in solutes between the
on the outside of a cell - the extracellular space. two sides.
And it helps regulate what comes in or out of the cell, which is called selective permeability. Osmotic pressure drives water from the hypotonic side - or the one with lower concentration of solutes - to
the hypertonic side - or the one with higher concentration of solutes.
Movement across the cell membrane can occur by passive transport, which requires no energy, and active
transport, which requires energy in the form of adenosine triphosphate, or ATP for short. But sometimes molecules need to be transported against their concentration gradient.
There are three types of passive transport - diffusion, facilitated diffusion, and osmosis. That requires energy - or active transport across the cell membrane.
Diffusion helps small, non-polar molecules, like oxygen and carbon dioxide, move across the membrane, Now, there are two kinds of active transport - primary and secondary.
from an area of high concentration to low concentration.
Primary active transport directly uses ATP as fuel, and it’s done by a family of enzymes called ATPases.
The difference in concentrations is known as the concentration gradient, and diffusion can occur as long as
this gradient exists, and stops once there are equal concentrations of the molecule on both sides. ATPases have the ability to “pump” out substances, such as ions, using ATP. Sort of like a candy dispenser.
You insert a coin, and candy pops out. Or, in our case, an ion pops out.
Facilitated diffusion helps larger molecules and polar molecules move across the membrane.
The most important example is the Na+/K+ ATPase, which is a “double action” pump - meaning that for
Facilitated diffusion uses transport proteins like channels and carrier proteins. each ATP molecule, it pumps 3 ions of sodium out of the cell, while at the same time pumping 2 ions of
potassium into the cell.
Channels are not very specific, and they can open or close to allow water and small polar molecules, like
ions, that are dissolved in it to pass through. This is an example of an antiport - because the two species of ions are pumped in opposite directions across
the membrane.
These channels open in response to certain stimuli - for example, the voltage gated calcium channels
respond when the electrical charges on the two sides of the cell membrane change. The resulting difference in concentrations of ions on either side of the membrane creates a concentration
gradient, but since ions also carry electrical charges, it’s considered an electrochemical gradient, and the
Normally, there are more negative ions inside the cell than outside, so the inside of the cell membrane is cell can use this in secondary active transport.
negatively charged, and the outside is positively charged.
Secondary active transport does not directly require ATP, but uses an electrochemical gradient - just like
When positive ions make their way inside the cell through one form of transport or another, the cell starts the one made using the sodium-potassium ATPase.
to depolarize gradually - so step by step, the membrane becomes more positive on the inside, and more
negative on the outside. An example is the sodium-glucose SGLT1 transporter, which pulls a molecule of glucose into the cell against
its concentration gradient, along with two sodium ions that move along their concentration gradient.
This change in the distribution of electrical charges makes the voltage gated calcium channels open and
allow water, a lot of calcium ions, and a few sodium ions inside the cell. Since both sodium and glucose go in the same direction, this transporter is called a symport.
When the entire membrane is depolarized, the channels close back up and inflow stops. Now, in addition, to pulling in individual molecules and ions, sometimes cells need to take in relatively large
substances, like proteins, fat droplets - and sometimes entire other cells!
In contrast, carrier proteins are very specific - they have special binding sites that only allow certain
molecules to bind to them, and they also have gates at both ends, which open sequentially. In these situations, the cell resorts to bulk transport - using endocytosis - where the cell membrane
invaginates and pulls in something from the outside or using exocytosis - where a vesicle from within the
An example of a carrier protein is the glucose transporter protein called GLUT4. cell pushing something out.
By default, the transporter is open to the outside, waiting for a glucose molecule to float by.
When a glucose molecule binds to a special site within the transporter, the outer gate closes, and the inner
gate opens. Summary
The glucose then unbinds, and floats freely into the cell, while the transporter will reset, awaiting for the
next glucose molecule. Okay, as a quick recap! Passive transport requires no energy, and can occur as diffusion or facilitated
diffusion which relies on carrier proteins or protein channels.
Since glucose is moving down its concentration gradient, this requires no energy!
There’s also Osmosis- which is when water moves from a hypertonic concentration to a hypotonic
concentration.
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Osmosis is considered a special case of facilitated diffusion.
Active transport, requires energy, and can either occur as primary active transport which uses ATP or
secondary active transport which relies on concentration gradients.
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So, Type I is found in the Bone, Skin, and Tendons.
Type II is in our cool Cartilage.

Extracellular matrix
Type III is in Reticulin – a type of fiber found in the Liver and the Lymphatic System - and Blood vessels.
Cells live within an environment called the extracellular matrix, and it's a bit like how homes have yards Type IV is found in the Basement membrane – a thin sheet of protein that separates different types of cells
and streets that surround them. like nerve cells from muscle cells.
Also, just like how lots of homes form a community, lots of cells form a tissue. Another type of structural protein is elastin, which is an elastic protein that allows connective tissues to
regain their original shape after stretching.
And there are different types of tissues - epithelial, connective, muscular, and nervous tissue.
Elastin is found in ligaments, blood vessels, skin, and lungs.
Each tissue has an extracellular matrix that’s got a unique composition that’s adapted for each tissue’s
unique needs. And the last structural protein is keratin - a pretty tough protein that’s found in our hair and nails.
Having said that, all of the different types of extracellular matrix are made up of three major molecules - Next, are the proteoglycans which are a group of molecules that have a protein core that’s attached to
adhesive proteins, structural proteins, and proteoglycans. chains of sugars called glycosaminoglycans.
First, there’s adhesive proteins, which help to stick the individual cells together and organizes the tissue Lots of glycosaminoglycans attach perpendicular to the core protein, so it looks a bit like the fibers of a test
into a neat structure. tube brush.
Now, adhesive proteins - like integrins and cadherins - are found on the cell’s surface and they’re like Examples of glycosaminoglycans include chondroitin, keratan sulfates and hyaluronic acid.
molecular velcro.
Now, proteoglycans mostly help to fill up the space between cells and the negative charge of
Cells use adhesive proteins to anchor themselves to other cells and to molecules in the extracellular matrix. glycosaminoglycans helps to trap water molecules.
Adhesive proteins also help communicate messages from the extracellular matrix to the cell. The result is that the proteoglycans plus water form a gel-like substance that hydrates and cushions the
cells, and it’s the main reason that it’s so abundant in cartilage.
For example, signals relayed by integrins can help a cell decide when it’s time to grow, divide, differentiate,
or even die - like in apoptosis.
Next, there are structural proteins which give our tissues their tensile and compressive strength.
Summary
Some examples are collagens, elastins, and keratins.
Collagen is the most common type of structural protein in the human body, mostly because it resists Alright, as a quick recap, the extracellular matrix is largely composed of adhesive proteins, structural or
tension and it can also stretch. fibrous proteins, and proteoglycans.
When collagen is made and released into the extracellular space, it’s in the form of a precursor called Adhesive proteins like integrins and cadherins help anchor the cell in place and link it to other cells.
procollagen. Collagen is the main structural protein in our body, and it gives tissues their firmness and resistance to
Procollagen is a protein made up of three polypeptide strands, each coiled into a left-handed helix, and then pressure.
all three are twisted together into a right-handed triple helix or "superhelix" with three loose strands at Other structural proteins are elastin - that allows tissues to stretch - and keratin, which forms the hair and
each end. nails.
Once procollagen is in the extracellular space, it encounters a tiny band of enzymes called collagen Finally, there are the proteoglycans - which keep cells hydrated and cushioned.
peptidases that cleave the loose strands at both ends of the procollagen protein, turning procollagen into
tropocollagen.
Once there are enough tropocollagen molecules, they bind with one another to form a stack of collagen
fibrils.
Collagen fibrils are arranged in different ways depending on the tissue, and when there’s a bunch of
collagen fibrils, they can join up to form a bigger tube called a collagen fiber.
The four most common types of collagen are I, II, III, and IV.
And you can use the mnemonic Be So Totally Cool, Read Books, Bro, to help you remember where each type
of collagen is located in the body.
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In the brain, the endothelial cells that line the inside of blood vessels also use tight junctions to form the
blood brain barrier, preventing harmful materials in the blood from reaching the central nervous system.
Cell-cell junctions Now, having said that, some tight junctions called leaky junctions do allow certain molecules to pass.
For example, the tight junctions in the proximal tubule of the kidney allow potassium, sodium, and chloride
Cell-cell junctions are protein structures that physically connect cells to one another. to slip by them.
Cell-cell junctions facilitate for cellular communication, boost tissue structure, help with transport of This is because the claudins and occludins in leaky junctions have ion pores that allow these ions to pass
materials between cells, or create an impermeable barrier for certain substances. through.
Cell-cell junctions are only found between immobile cells of organs and tissues-- so mobile cells like sperm Next are gap junctions, which are sort of like sky bridges that might connect two adjacent buildings.
and macrophages don't have these structures.
A single gap junction is made up of several connexin proteins, which are transmembrane proteins.
Cell-cell junctions are most abundant in epithelial tissue, which is found in skin and the innermost layer of
the gastrointestinal tract. These connexins create a tubular structure that allows charged particles like ions and small molecules like
cytokines to pass between cells. This allows cells to rapidly communicate with one another.
However, these structures are also found in other organs like the heart, kidneys, and liver.
For example, in cardiac myocytes, or heart muscle cells, ions from one cell can move through a gap junction
The three types of cell-cell junctions are adherens junctions, tight junctions, and gap junctions. to an adjacent cell, and that can help create a coordinated heart contractions.
Adherens junctions are formed by groups of proteins that anchor cells together side by side and prevent Another example, is when an infected cell sends molecules called cytokines through gap junctions to
their separation - making them “adhere” to one another. initiate apoptosis or programmed cell death in a neighboring cell.
Adherens junctions have three major components. This is called the bystander effect, and it’s an effective way to prevent the spread of an infection to
neighboring cells - which can’t host the pathogen if they’ve already died.
The first component are long filamentous proteins called actin filaments that are part of the cytoskeleton
and help give a cell its shape.
The second component is protein plaques, which are protein structures within the cytoplasm that are
anchored to the plasma membrane that bind to the actin filaments. Summary
Third, are transmembrane proteins called cadherins which attach to the protein plaques on one side and
transverse the plasma membrane and connect to cadherins of an adjacent cell, linking the two together. Alright, as a quick recap, cell-cell junctions are found in non-mobile cells.
In this way, adherens junctions create a continuous network of interconnected cells via actin, which Adherens junctions provide extra resistance in tissue under a lot of force, tight junctions selectively block
ultimately ties all these cells together to prevent their separation and provides extra strength. the passage of water, proteins, and bacteria, and gap junctions allow cells to communicate with each other
by allowing signal molecules to pass through.
This is particularly important in tissues that are exposed to constant shearing or abrasive forces like the
skin or gastrointestinal tract.
It’s a bit like the reinforcing steel bar or rebar that sits within cement blocks to give a wall extra strength.
Now, tight junctions, also known as occluding junctions, are protein structures that seal two plasma
membranes of adjacent cells together.
As a result, they prevent water, small proteins, and bacteria from passing in between two adjacent cells.
Tight junctions are formed by proteins called claudins and occludins that are embedded in the plasma
membranes of both cells.
The proteins on one membrane can interlink with the proteins on the membrane of an adjacent cell and
seal them together.
Typically, this seal happens only in one area near the apical surface of the cells and not across the entire
length of the membrane.
Tight junctions are especially important in places like the gastrointestinal tract, where they help to prevent
bacteria or digestive enzymes from entering the deeper tissues or water from seeping out of the intestine.
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The lysosome and the phagosome fuse together, merging their contents forming a structure known as the
phagolysosome.
Endocytosis and exocytosis Inside the phagolysosome, lysosomal enzymes start destroying the bacteria with the help of an acidic pH.
After it’s all over, the lysosome heads over to the cell membrane to expel the leftovers out into the extracellular
Cells transport material in and out across their cell membrane, which is a barrier made up of a double layer of space - like a cellular burp.
lipids with embedded protein and carbohydrate components.
Pinocytosis, on the other hand, means “the cell drinks”.
Some molecules can diffuse across the membrane, or be transported across with the help of membrane-bound
proteins. In pinocytosis, the cell’s plasma membrane invaginates to form a small cup around the portions of extracellular
fluid and solutes that are dissolved in it.
For transport of larger cargo, cells use endocytosis and exocytosis to transport material in and out of the cell,
respectively. Then the edges of the cup come together, forming a vesicle.
And there are roughly five categories of molecules that try to get across the cell membrane. Since the cell is not really “eating” anything other than the occasional solute, the result is not a phagosome, but
merely a vesicle.
Small non-polar molecules, like oxygen or carbon dioxide, are able to diffuse rapidly through the cell membrane.
The pinocytosis vesicle is much smaller than a phagosome.
Small, polar molecules, like water, can cross as well, but very slowly.
Also, unlike phagocytosis, pinocytosis is a non-specific way for cells to take in solutes - so whatever solutes are
Large, nonpolar molecules like Vitamin A, are also very slow to cross the cell membrane. hanging around in the extracellular fluid get pulled inside the cup.
And large, polar molecules, like glucose, as well as highly polar, charged ions like Na+, K+, Cl-, or molecules that Once inside the cell, motor proteins like kinesin, or dynein carry the pinocytosis vesicle using ATP to go deeper
possess a charge, like amino acids are highly unlikely to get across a cell membrane on their own. into the cytosol.
So many of these molecules - some common ones being water, glucose, and ions, pass through the membrane At the same time, the vesicle slowly releases the extracellular fluid and the solutes into the cytosol.
using transport proteins.
Now, finally, sometimes endocytosis involves special receptor proteins on the cell membrane - so it’s called
Examples of transport proteins include channels, like aquaporins - a water channel and chloride channels which receptor-mediated endocytosis.
let chloride ions get across membranes, or carriers - such as the glucose transporter.
Some molecules are taken in this way, like transferrin, which is an iron-binding protein, or low density
However, when the cell needs to transport a lot of molecules, or a very big molecule, it resorts to bulk transport, lipoproteins - or LDL, which contain cholesterol.
which comes in two flavors: endocytosis and exocytosis.
As an example, let’s see how this goes for LDL. Now, on the surface of the cell membrane, there are indented
Endocytosis is a process that cells use to engulf extracellular material. pits that have specific receptors for molecules like LDL.
And exocytosis is the opposite process, during which cells expel material into the extracellular space. These pits are covered on the intracellular side of the cell membrane by a layer of clathrin proteins - so they are
also called coated pits.
Both endocytosis and exocytosis need energy in the form of adenosine triphosphate or ATP, used in the
movement of the substances in and out of the cell. Now, let's say LDL binds to its receptor in one of these pits. The edges of the pit start coming together.
There are three types of endocytosis - phagocytosis, pinocytosis and receptor-mediated endocytosis. At the same time, the clathrin proteins inside the cell link up to another like a sturdy shell around the forming
vesicle.
Phagocytosis - where phago- means to eat - is used by white blood cells like macrophages and neutrophils that
patrol the body looking for debris, bacteria and dead cells to eat. Once the vesicle pinches off from the cell membrane, the clathrin proteins detach from it and go back to the cell
membrane.
So let's imagine that a macrophage comes across a particularly bothersome Streptococcus - first, the Strep
attaches to macrophage receptors on its cell surface. Inside the cell, the vesicle merges with an organelle called the endosome.
The macrophage then extends arm-like projections called pseudopods around the Strep - like a death hug. Endosomes are similar to lysosomes, in that they also fuse with ingested vesicles, but they can also do
something else: endosomes can separate the LDL particle from the LDL receptor it bound to.
Then the Strep is slowly engulfed by the cell membrane, which invaginates to form a vesicle on its inner side.
This is because the endosome has a proton pump that uses ATP to generate a low pH within, which causes the
The vesicle then separates from the cell membrane forming a phagosome.
LDL to separate from the LDL receptor.
During this step, an electron pump uses ATP to pump protons into the phagosome, lowering the pH inside.
At that point, the vesicle splits into two vesicles, one vesicle that has all of the LDL that’s been brought into the
In the cytoplasm, the phagosome encounters an organelle called a lysosome, which contains digestive enzymes. cell, and the other vesicle that has all of the LDL receptors.
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The LDL-filled vesicle goes to the lysosome for digestion, while the one containing the LDL receptors goes back
and releases the receptor back on the surface of the cell membrane.
This is called receptor recycling - because now the LDL receptor can bind to another LDL molecule, and the cycle
can repeat itself.
Kinda like washing a dirty dish and using it again, instead of using new plates for every meal.
Now, exocytosis, on the other hand, starts deep within the cell, in an organelle called the Golgi apparatus, that
takes the proteins, lipids, and hormones that are generated in the rough ER and smooth ER, and packages them
into a vesicle that can be ziplined around the cell using the cytoskeleton.
The cytoskeleton is made out of proteins like microfilaments, microtubules, and intermediate filaments, which
all provide structural stability.
The cytoskeleton is also very dynamic, allowing the cell to change shape by selectively extending and contracting
filaments - which is important in some cell functions, like muscle contraction, cell division, and even cell
movement!
The cytoskeleton also helps structures within the cell move from one area to another.
Now, there are secretory vesicles which move molecules out of the cell with the help of motor proteins like
kinesin, or dynein, which pick up the vesicle and carry it towards the cell membrane along microtubules using
ATP as fuel.
The vesicle moves towards the cell surface, fuses with the cell membrane, and ruptures on its external side,
spilling its contents into the extracellular space.
Summary
Alright, as a quick recap, endocytosis refers to the process in which cells engulf extracellular material, and there
are different forms of endocytosis like phagocytosis, pinocytosis and receptor-mediated endocytosis.
Exocytosis refers to the process in which cells expel material into the extracellular space.
Both endocytosis and exocytosis require ATP to happen.
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Once there enough water that the concentration of salt on the two sides is equal once more, then the net
movement of water across the membrane goes back to being zero and the two sides are isotonic to one
another again. So far so good.
Osmosis
But now, there’s the bigger question of why water molecules end up staying more on side A, and it has to do
with kinetic energy and entropy.
Osmosis is a group of people that take complicated medical topics and teach them in an organized and
effective way so that the information seeps into your brain and leads to longer retention… oh wait, not that Kinetic refers to the fact that water molecules as well as sodium and chloride ions have a tendency to want
Osmosis? to move around.
Well, then, simply put, osmosis is how water molecules move across a semipermeable membrane that And entropy plays a role because this movement is disordered or random so that over time the water
separates two solutions. molecules and ions move every which way.
It can be thought of as passive diffusion of water and it requires no energy. You can think of each molecule or ion like a toddler - you know it’s going to move but you can’t predict it’s
next move or where it might end up two minutes later!
When water molecules move like this, they end up equalizing the concentrations of the solutions on either
side of the membrane. Now, going back to the experiment. When we initially added more salt there were relatively more sodium
and chloride ions on the hypertonic side - side A.
This is possible because a semipermeable membrane, like the cell membrane for example, is kinda like a
sieve with pores that let small molecules like water across, but not larger molecules or ions like sodium and Now we know that, sodium and chloride ions are too large to pass through the pores in the membrane.
chloride.
But in addition to that, and here’s the important part, the ions actually end up slightly blocking or
So let's say that we’re looking at a lab beaker that is filled with a salt water solution, and we separate it in interfering with water molecules that want to go from one side to the other.
two compartments - A and B - with a semipermeable membrane in the middle.
That’s because the ions are so large that as they’re bouncing around, they literally get in the way of the
Now, first off - the salt which is sodium chloride will separates out into sodium ions and chloride ions once door.
it’s in the water.
It’s like a partygoer that is unable to leave a party but also blocks the five foot area around the door -
And since the concentration of sodium and chloride ions is the same on either side of the membrane, we say making it hard for others to leave the party as well.
that A and B are isotonic to each other.
But remember that these ions are not physically stuck to the hole between the two sides, they’re just
Now, inside the two compartments, water molecules and sodium and chloride ions are moving around and knocking water molecules in that area out of the way through their random bouncing movements.
bouncing off each other.
To make matters worse, the sodium ions are positively charged and they actually attract the slightly
It’s a bit like two big dance parties happening in two adjacent warehouses that are connected by doors that negative charge of the oxygen atom in a water molecule.
are semipermeable - meaning that the water molecules can get through but not the larger sodium and
chloride ions. Similarly, chloride ions are negatively charged and they attract the slightly positive charge of the hydrogen
atoms in a water molecule.
Now some of the water molecules may go through one of these doors to go from party A to party B, and
some water molecules might go the other direction from party B to party A. If these water molecules are somewhat attached to an ion that can’t get through the membrane, they will
also be hindered from getting through the membrane.
But the truth is that the water molecules aren’t particularly drawn to either compartment, because crossing
the membrane to go one way is just as easy as crossing the membrane to go the other way. So in short, the ions that can’t get through interfere with the water molecules from leaving the party.
We call this point equilibrium - and in this particular state the net movement of water across the membrane And since the concentration of ions is higher on side A, then side B, more of this interference is happening
is zero. on side A.
But what if we were to add some additional salt - or sodium chloride - inside only compartment A? As a result more water molecules are ultimately able to get from B to A, then the other direction.
A now has more solute than B, and we would say that A is hypertonic compared to B, and conversely that B All in all, this means that when there’s a difference in concentrations, water molecules move from an area of
is hypotonic compared to A. low solute concentration to an area of high solute concentration.
And what we’d notice over time is that because A has more sodium and chloride ions its osmotic pressure Put differently, they move from the hypotonic side, where there’s relatively more water, to the hypertonic
increases. side, where there’s relatively less water.
The result is that we’d see a bigger net migration of water molecules over to side A. Now, it just so happens that osmosis is super important for our cells.
We say “net” migration, because water molecules are still going back and forth between the two sides, but For example, let’s say that we put a red blood cell, in a hypertonic solution like vinegar.
overall, more water molecules will now end up staying on side A.
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Right away, there would be a net movement of water molecules out of the cell, leaving our cell dried out
and shrivelled.
On the other hand, let’s say we put a red blood cell in a hypotonic solution like pure water.
This time, there would be a net movement of water molecules into the cell, making it swell up and
eventually burst. Again, not a good way to go.
Like goldilocks, our cell would prefer something in the middle - an isotonic solution - like the intravenous
fluids that are used in hospitals.
These fluids have sodium chloride, in a concentration that’s similar to the solute concentration inside the
cell.
In this situation, the net movement of water inside and outside of the cell is zero, so the cell continues to
live comfortably.
Summary
Alright, as a quick recap: osmosis refers to the movement of water molecules across a semipermeable
membrane that separates two compartments of fluid.
It can be thought of as passive diffusion of water and it requires no energy.
The side that has more solutes will prevent water molecules from leaving, and as a result there will be a net
movement of water to the hypertonic side.
Over time the movement of water molecules from the hypotonic to the hypertonic side will equalize the
concentrations.
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Now the formula that tells us the equilibrium potential for each ion called the Nernst equation, and it’s Vm
(for membrane) equals 61.5 times the log of the concentration of the ion outside the cell, divided by the
concentration of the ion inside the cell, for an ion with a single charge like sodium, and Vm equals 30.75
Resting membrane potential times the log the concentration of the ion outside divided by the concentration of the ion inside for an ion
with a double charge like calcium.
Each cell in the human body is wrapped in a membrane that separates the inner environment and outer For the four main ions that affect the cell’s resting membrane potential, which are potassium, sodium,
environment, and positively and negatively charged ions aren't equally distributed on both sides of the chloride, and calcium, the concentrations are 150 mMol/L, 10 mMol/L, and 4 mMol/L, and less than
membrane. 1μMol/L on the inside of the cell, and 5 mMol/L, 142 mMol/L, and 103 mMol/L, 5 mMol/L on the outside of
the cell.
Fundamentally, it’s these differences in concentration and charge as well as permeability across the
membrane that establishes the cell’s resting membrane potential. Plugging those into the formula, we get equilibrium potentials of -92 mV, +67 mV, 86 mV, and +123 mV.
Generally speaking there is a higher concentration of Na+ or sodium, Cl- or chloride, and Ca2+ or calcium One thing to note, though, is that since chloride ion is negative, the equilibrium potential actually gets
on the outside of a cell, and a higher concentration of (K+) or potassium and (A-), which is just what we just flipped, so it’s actually -86 mV.
write for negatively charged anions, on the inside of a cell.
These all represent the charge in the cell needed to balance the movement of each of these ions based on
These anions include a variety of amino acids and proteins that are produced by the cell. the concentration gradients, and to make it clear the concentration gradients themselves are potassium
moving out, calcium moving in, sodium moving in, and chloride moving in, since remember there’s low
Let’s start with the sodium-potassium pump which uses ATP to move three sodium ions out of the cell for
concentration of potassium outside the cell, but high concentration of calcium, sodium, and chloride outside
every 2 potassium ions that it moves into the cell, this is the workhorse of the cell and it helps establish the
the cell, and concentration gradients move from high concentration to low concentration.
concentration gradient for potassium and sodium.
Alright, so the actual resting membrane potential of the cell will end up being somewhere in between all
Let’s focus on potassium, which has a concentration of 150 mMol/L on the inside of the cell and about 5
these individual membrane potentials, depending on how much of each of these ions is moving across the
mMol/L on the outside of the cell.
membrane at a given time.
With so much potassium within the cell relative to outside the cell, there will be fairly strong concentration
This differs depending on the cell that we’re talking about, but in general potassium makes up the biggest
gradient moving potassium ions out of the cell.
proportion of ions moving across the membrane, while the other three have way less moving across at any
Although these ions can’t simply diffuse through the phospholipid bilayer membrane, it turns out that given time.
potassium can get across the membrane using potassium leak channels and inward rectifier channels that
Alright so of all the ions moving across the cell membrane through leak channels, let’s say that 90% of them
are scattered throughout the membrane.
are potassium ions, whereas only 1% are calcium ions, 1% are sodium ions, 8% are chloride ions.
So using those channels, the concentration gradient pushes potassium out of the cell, and that potassium
Now we can take these proportions and multiply them by the equilibrium potentials and then add up the
brings with it some positive charge and leaves behind unpaired anions which carry negative charge
total to get the resting membrane potential of the cell.
because they aren’t able to go through the leak channels.
In this case it works out to 90% of -90mV (-81 mV) plus 1% of 123 mV or 1.23 mV, plus 1% of 67 mV which
Over time as more potassium ions leave the cell, a negative charge builds up within the cell and this starts
is 0.67 mV, and plus 8% of -86mV which is -6.88mV, which gives a grand total resting membrane potential
to attract positively charged potassium ions back into the cell, and this is called the electrostatic gradient.
of -86 mV.
This electrostatic gradient is established with the movement of relatively few ions, so it doesn’t upset the
Now this resting membrane potential is usually closest to whichever ion is most permeable across the
overall concentration gradient that was already established.
membrane, which in this case is potassium, right?
For potassium, the exact point when the potassium moving out of the cell due to the concentration gradient
But by changing the cell’s permeability to ions by adding or removing ion channels, a cell can actually
equals the potassium moving back into the cell due to the electrostatic gradient is called the equilibrium
change its resting membrane potential.
potential or nernst potential for potassium, and it’s about -92 mV.
In other words, -92 mV is the electric potential for attracting potassium into the cell that is needed to
balance the concentration gradient that is pushing potassium out of the cell.
Summary
So the equilibrium potential of an ion is dependent on two things: the concentration gradient for the ion
and the cell being permeable to that ion.
Okay, as a quick recap, an ion’s equilibrium potential is the point where its concentration gradient equals
If we’re only dealing with a single ion, then the equilibrium potential for the ion equals the resting its electrostatic gradient, and can be calculated using the Nernst equation.
membrane potential for the cell.
The cell’s resting membrane potential is therefore a summation of each individual ion’s equilibrium
In reality, though, there are multiple ions that have concentration gradients and are permeable across the potential, depending on each ion’s relative permeability.
cell membrane, each of which has its own equilibrium potential.
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G proteins are made up of three subunits called alpha, beta, and gamma, sort of like a flower with three petals.
The alpha and the gamma subunits are anchored to the cell membrane and keep the G protein right next to the
Cell signaling pathways receptor.
G proteins bind to guanosine diphosphate or GDP when they’re inactive.

To make a multicellular organism, cells must be able to communicate with one another, and to do it cells often
send out tiny chemical signals that act on the receptors on other cells. When the alpha subunit is bound to GDP, the three subunits stay together, so the flower is closed.
Signals can be classified according to the distance between the signaling cell and the target cell. But when the ligand binds, the G-protein coupled receptor changes its shape, and this allows the G protein to
release GDP and bind GTP instead, activating the protein.
Autocrine signals are produced by a cell and go to its own receptors, so the cell sends a signal to itself.
When the alpha subunit is bound to GTP, the alpha subunit separates from the beta and gamma subunits, like
Paracrine signals are produced by a cell and go to target cells that are nearby. one petal opening and separating from the others.
And endocrine signals are produced by a cell and go to target cells that are further away. When that happens, the alpha subunit is free to interact with other proteins - it stimulates some while inhibiting
others.
Examples of these include hormones that are secreted into the bloodstream, as well as cytokines that can be
released at the site of injury and act on the brain to cause a fever. But, to act on other proteins, the alpha subunit turns GTP into GDP, and when that happens the three subunits
come together again - the flower closes - and the G protein is turned off.
Signaling molecules or ligands can be hydrophobic, meaning that they tend to repel water, or hydrophilic,
meaning that they tend to stay in water. Overall, there are three types of G proteins: Gq, Gi, and Gs, and each one stimulates and inhibits a different set
of enzymes and molecular pathways.
Hydrophobic signalling molecules can't freely float in the extracellular space, so they’re brought to the target
cells by carrier proteins. The Gq protein activates the enzyme phospholipase C, which is found in the cell membrane.
Hydrophobic molecules can diffuse across the cell membrane and bind to receptor proteins inside the target cell Phospholipase C then cleaves a phospholipid called phosphatidylinositol 4,5-bisphosphate into inositol
- either in the cytoplasm or in the nucleus. trisphosphate and diacylglycerol.
Most signal molecules are hydrophilic, so they can freely float in the extracellular space to reach the target cells, Inositol trisphosphate is soluble and diffuses freely through the cytoplasm and into the endoplasmic reticulum
but are then unable to cross the cell membrane. where it opens up calcium channels.
So to pass on the signal, hydrophilic molecules bind to receptors on the cell surface. Since the calcium concentration is higher in the endoplasmic reticulum than in the cytoplasm, calcium flows out
of the endoplasmic reticulum to the cytoplasm.
These receptors are transmembrane proteins, with an extracellular end that binds to the ligand, and an
intracellular end that triggers a signaling pathway inside the cell. The increased calcium concentration in the cytoplasm changes the electrical charge of the cell and can lead to
depolarization.
We can think of the cell signaling pathway in three stages.
Meanwhile, diacylglycerol remains attached to the cell membrane and binds to the enzyme protein kinase C,
The first stage is reception, which is when the target cell’s receptor binds to a ligand. It’s like a key fitting into a
which also relies on calcium to fully activate.
lock.
Once calcium levels in the cell go up, protein kinase C starts to activate proteins by adding phosphoryl groups to
Then there’s transduction, which means that the receptor protein changes in some way and that activates
them.
intracellular molecules - the second messengers.
Next is protein Gs which stimulates the enzyme adenylate cyclase.
The third stage is the cell’s response to the signal.
Activated adenylate cyclase takes adenosine triphosphate or ATP, and removes two phosphate molecules
Zooming into these transmembrane receptors, there are three major classes: G protein coupled receptors,
transforming it into cyclic adenosine monophosphate or cAMP.
enzyme-coupled receptors, and ion channel receptors.
cAMP moves throughout the cytoplasm and binds to the enzyme protein kinase A.
G-protein coupled receptors are seven pass transmembrane receptors.
Protein kinase A has two parts - a regulatory subunit and a catalytic subunit, and cAMP specifically binds the
These are really long proteins that have one end that sits outside the cell and binds the ligand, then the snake-
regulatory subunit of protein kinase A.
like protein dips in and out of the cell membrane seven times, and finally ends on the inside of the cell.
When cAMP binds it makes the regulatory subunit dissociate from the catalytic subunit of protein kinase A.
The end of the G-protein coupled receptor that’s within the cell activates intracellular proteins called guanine
nucleotide-binding proteins or G proteins. It’s like pulling the pin out of the fire extinguisher allowing it, in this case the catalytic subunit, to do its job.
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So after dissociating, the catalytic subunit of protein kinase A is free to phosphorylate target proteins that trigger Alright, as a quick recap, autocrine signals target the same cell, paracrine signals target nearby cells, and
a cellular response. endocrine signals target distant cells.
Finally, there’s the protein Gi, which is also bound to adenylate cyclase - but in this case, inhibits it, causing Hydrophobic ligands are able to diffuse across the cell membrane and bind to receptor proteins inside the target
negative feedback on protein Gs. This is particularly important in helping to inactivate cells. cell.
Next are the enzyme-coupled receptors. They’re usually single-pass transmembrane proteins, meaning that they Hydrophilic ligands are unable to cross the cell membrane, so they must bind to transmembrane receptors,
have only one transmembrane segment, and their intracellular end has intrinsic enzyme activity. which have an intracellular end that triggers a signaling pathway inside the target cell.
In other words, enzyme-coupled receptors have two parts - one domain is the receptor and the other domain is There are three major transmembrane receptor classes: G protein coupled receptors, enzyme-coupled
an enzyme. receptors, and ion channel receptors.
Each domain has a separate function, like a swiss army knife composed of both a knife and scissors.
The enzymatic domain is usually a protein kinase that phosphorylates the receptor domain.
Now, there are three main types of enzyme-coupled receptors, based on the amino acid the receptors get
phosphorylated at.
The first group are the receptor tyrosine kinases. These are the most common enzyme-coupled receptors, and
there are many subfamilies.
Receptor tyrosine kinase are generally molecules that can’t phosphorylate their own tyrosine side chains.
When a ligand binds, two receptor chains come together and dimerize, and they cross-phosphorylate one
another at multiple tyrosine residues.
This triggers a conformational change that creates high-affinity binding sites for the second messengers, which
can also be phosphorylated and activated, triggering the signaling pathway.
Next, are the tyrosine kinase associated receptors which work in nearly the same way as receptor tyrosine
kinases, and their name even sounds almost the same.
The key difference is that they have no intrinsic enzyme activity. Instead they’re associated with cytoplasmic
tyrosine kinases.
When the receptors bind their ligand, the cytoplasmic tyrosine kinases phosphorylate various target proteins to
relay the signal.
Finally, there are the receptor serine/threonine kinases and they have a serine/threonine kinase domain on their
intracellular end.
There are two classes of these receptor serine/threonine kinases - type I and type II - which are structurally
similar.
Ligand binding brings the two together together so that the type II receptor can phosphorylate and activate the
type I receptor, which in turn recruits and phosphorylates various target proteins to relay the signal.
Finally, there are the ion channel receptors which are generally closed, but then open up once they bind a
specific ligand.
They allow ions like chloride, calcium, sodium, and potassium to passively flow down their gradient.
This leads to a shift in electric charge distribution inside the cell, triggering a cellular response.
Summary
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First, there’s euchromatin, which is loosely packed and contains genes that the cell frequently transcribes
and translates.
Nuclear structure In other words, euchromatin contains the genes that the cell frequently needs to copy from DNA into
messenger RNA or mRNA and then into a protein.
The nucleus is a cellular organelle, found in eukaryotic cells that contains most of the cell's genetic material Second, there’s heterochromatin, which is densely packed and contains genes that the cell rarely
in the form of DNA. transcribes and translates.
DNA contains the genes, which are, essentially, blueprints for various proteins that the cell needs to live. Now, chromatin is actually made out of 46 separate DNA molecules each of which is called a chromosome.
Most cells in the human body have a single nucleus. Most of the time, the cell is not dividing, and the chromosomes are in an intertwined, loose spaghetti-like
state.
But some cells, like red blood cells, have no nuclei, whereas some like skeletal muscle and liver cells have
more than one nucleus. During cellular division, the 46 chromosomes condense and double up the amount of DNA within the
nucleus by creating an identical copy each - now called “sister chromatids” - so while there’s still 46 of
Now, the nucleus is surrounded by the nuclear envelope. them, they are made out of two chromatids each, and take on that familiar “X” shape.
Inside the nucleus, there is the nucleoplasm - a liquid environment very similar to the cell's cytoplasm. The two sister chromatids are identical to each other and to the original genetic template, and they join
together in the center in a region called the centromere - but they still make up a single chromosome.
Suspended in the nucleoplasm, there’s chromatin, which is the densely packed DNA, and also the nucleolus
- which makes ribosomes, which, in turn, help build proteins. After the cell divides, each resulting daughter cell gets one copy of the genetic material - so 46
chromosomes made up of a single, loose spaghetti-like chromatid thread each, now called the chromosome
Let’s start with the nuclear envelope, which has an inner and the outer membrane - both of which are made
again - and we’re back to regular cell business.
of phospholipid bilayers.
It can be a bit confusing because the structure with two sister chromatids connected together is called a
The outer membrane has lots of anchoring proteins that allow the nucleus to remain suspended within the
chromosome, and when the chromatids split up the structure with a single chromatid is also called a
cytoplasm - like a puppet on strings.
chromosome.
The inner membrane is covered by the nuclear lamina - which is a network of lamin proteins.
So, now let’s focus on chromatin itself - it’s actually a long, loopy, and continuous “fiber”.
These lamin proteins are thin filamentous proteins that create a dense protein web within the nucleus - a
Zooming further in, the “fiber” actually resembles the spring-like cord of an old telephone - so, a tight
bit like dense spider web.
helical fiber.
The nuclear lamina provides something for the chromatin to drape itself over, a bit like caterpillars hanging
Going even deeper, the “cord” itself is made up of tight loops of DNA wrapped around protein structures
out all over those spiderwebs.
called histones.
The nuclear envelope is selectively permeable - meaning, it allows some things to pass through, while
Basically, 8 histones get packed together in 4 stacks of 2, and the double-helix DNA wraps around them
preventing others.
twice.
There are also relatively large nuclear pores, and each pore has a nuclear pore complex lining it on the
Together these 8 histones and the DNA wrapped around them are called a nucleosome - and they look a bit
inside, made out of proteins called nucleoporins, and it kinda resembles a basketball hoop with a net.
like beads on a string.
So large molecules like nucleic acids and proteins aren’t able to come and go easily, but small water soluble
Now, the histones help control the DNA that runs around through them.
molecules have no trouble.
If the histones have a methyl group attached to them, they prevent that chunk of DNA from getting
The main role of the nucleus is to house the DNA - it is, essentially, a central genetic library with
transcribed.
instructions on how, when and what kind of proteins the cell needs to make in order to live and perform its
functions. Finally, we have the nucleolus, which contains a special kind of DNA called ribosomal DNA, or rDNA, which
can be transcribed into ribosomal RNA - or rRNA.
These instructions come from one of our DNA molecules, that are really, really long - over 2 meters each
when fully stretched. rRNA is then folded around some proteins inside the nucleolus to create a molecular machine called the
ribosome.
So our cells have to rely on a few packing tricks to compress all that to fit inside nucleus.
The ribosome can float out of the nucleus, where it joins other ribosomes in the cytoplasm.
Here’s where chromatin comes in. Essentially, chromatin is a fine matrix of very densely woven and
compressed DNA. Interestingly enough, the assembled ribosome is the largest structure that can pass through a nuclear pore.
There are two types of chromatin. The ribosomes, can then use the mRNA copies to produce proteins!
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The ribosome converts mRNA into a string of amino acids which can form a protein in a process called
translation.
As it progresses, it will inject the protein into an organelle known as the endoplasmic reticulum.
Inside, the protein gets folded into shape and modified as needed, to take its role inside or outside of the
cell.
Summary
Alright, as a quick recap. The nucleus is surrounded by the nuclear envelope, which has an inner and an
outer membrane.
Nuclear pores run through the envelope, and they control the kind and flow of molecules that are allowed
in and out of the nucleus.
Inside the nucleus, there is DNA, which is tightly packed into chromatin.
Inside the nucleus there’s also the nucleolus, which assembles protein-making ribosomes.
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At the end of mitosis, the cell has two sets of chromosomes that each sit in their own nucleus.
A ring of actin filaments then forms around the center of the cell between the two nuclei.
Cytoskeleton and intracellular motility
This ring uses the sliding movement of actin and myosin to help constrict or squeeze the cell so that it pinches
off into two new cells.
The cell is the basic unit of life, that can replicate on its own.
Next, are the microtubules which are the thickest and largest of the protein structures in the cytoskeleton.
The human body alone has over 200 different cell types - from long skinny neurons that can grow over 1 meter
long to myocytes or heart muscle cells that contract to let you to flex your muscles. Microtubules are made of alternating round proteins called α- and β-tubulins - which form long strands called
protofilaments.
But despite their differences, they share many features, including the cytoskeleton.
Thirteen of these protofilaments come together to form a single microtubule.
The cytoskeleton is a network of proteins within the cell.
Microtubules stretch to and from every corner of the cell, which allows them to be used like railroads for
The cytoskeleton gives each cell its shape and anchors organelles in place - keeping everything sturdy - a bit like intracellular transport.
the frame for a house.
For example, proteins like kinesin and dynein which pick up vesicles full of proteins, lipids, or hormones, and
But it's also a dynamic network, which can change shape when the cell wants to move, contract, divide, or pull in carry them on microtubules either to or from the cell membrane to specific organelles - like the Golgi apparatus.
or push out molecules. Imagine if your house could do that - perhaps it would get up and walk away during an
earthquake! Microtubules can also resist a lot of compression force and still maintain their shape, so they’re like the steel
beams that support and give a building its shape.
So the cytoskeleton is pretty special and it’s made up of three proteins: actin filaments, intermediate filaments,
and microtubules. Microtubules also play a role in cell division.
Actin filaments are the thinnest of the three proteins, so they’re also called microfilaments. During cell division there are two centrosomes, and each centrosome is made out of two centrioles.
They’re made up of two strands of actin proteins arranged in a long twisting chain like a twisted necklace. Each centriole is in turn made up of nine sets of microtubule triplets, and each microtubule triplet is at a slight
angle with respect to the next microtubule triplet.
The actin filaments connect to one another to form a network - like a spider's web - that’s located just below the
cell membrane. Now, during cell division, each chromosome is made up of a pair of sister chromatids which are joined together
at a region called the centromere.
The actin filaments slide closer together and further apart, allowing the cell to change shape during muscle
contraction. Now, at the centromere there’s a specific protein complex called the kinetochore.
Not surprisingly, muscle cells have plenty of actin, as well as another protein called myosin. To help the two sister chromatids separate from one another, microtubules from the centriole polymerize in the
direction of the kinetochores.
Myosin filaments bind to actin filaments, and that’s what allows the actin to slide closer together and further
apart. It looks a bit like a fishing line being cast out to it’s target, and then the line gets reeled in pulling the kinetochore
and it’s attached sister chromatid away from it’s partner chromosome.
And ultimately, that makes the muscle cells shrink and stretch during muscle contraction and relaxation.
Ultimately, this gives rise to two sets of single-chromatid chromosomes, one for each of the daughter cells.
Similarly, sometimes these networks change their shape and that allows cells to move.
Microtubules also help with cell movement - and that’s because centrioles also form at the base of flagella and
White blood cells like neutrophils use extensions called pseudopodia, or false feet, to crawl in and out of blood cilia.
vessels - a process called diapedesis.
Flagella form the sperm cell’s tail – which wiggles to help sperm move.
The way that works is that the neutrophil’s actin filaments grow rapidly through the polymerization of many
actin monomers in one direction, to push out the cell membrane and create a foot. Cilia, on the other hand, are shorter than flagella and can be non-motile or primary cilia or they can be motile or
secondary cilia.
This newly created foot wedges between the endothelial cells that make up the blood vessels.
Nonmotile cilia are found on photoreceptor cells in the human eye and they help with the absorption of
The neutrophil then begins to squeeze through, until it reaches the other side. photons, which then the brain converts into a color image.
It’s a bit like squeezing between two fence poles to sneak into an amusement park, rather than paying Motile cilia, on the other hand, can be found on cells like the ones that line the fallopian tubes, which slowly
admission. sway and drag the egg cell, fertilized or not, towards the uterus.
Not saying that you should do that. Now, actin filaments also play a role in mitosis - or cell division.
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Finally, there are the intermediate filaments, which fall in between actin filaments and microtubules in terms of Intermediate filaments fall between actin filaments and microtubules when it comes to diameter and they
size. provide strength to the structure of the cell.
Intermediate filaments are made of interlaced threads of protein - like a rope. And finally, there are microtubules, which are the thickest of the three. Microtubules, give cells their overall
shape, form centrioles, and helps in the transportation of vesicles.
This makes intermediate filaments stronger than actin filaments, but also less dynamic.
Intermediate filaments mostly fasten various organelles like the nucleus in place within the cell.
Intermediate filaments also help anchor cells to neighboring cells, through cell to cell junctions.
They also help anchor the cells to their surrounding environment, the extracellular matrix.
Intermediate filaments are less dynamic than actin filaments and microtubules, so they tend to degrade slowly
and last longer within the cell.
Now, unlike actin filaments and microtubules, intermediate filaments are made of many types of proteins
depending on the cell type.
They are classified by their molecular similarities into type I, II, III, IV, V, and VI.
Types I and II are the keratins and they make up the main structural component of hair, nails, and the outermost
layer of the skin.
Type III includes the most common of all intermediate filaments - vimentin. Vimentin is found in cells like
smooth muscle cells, fibroblasts, and white blood cells.
Another type III protein is desmin and it forms the basic unit of the skeletal and cardiac muscle cells - the
sarcomere that makes muscles contract.
A third type III intermediate filament protein called glial fibrillary acidic protein, and it’s found in supporting cells
in the central nervous system, like astrocytes.
A fourth type III intermediate filament protein called peripherin is found in neurons of the peripheral nervous
system.
Type IV intermediate filaments include synemin, also called desmuslin, which provides resistance to mechanical
stress in cells - so while they are found in all cells, they’re especially abundant in skeletal muscle cells.
Another muscle-specific type IV intermediate protein is syncoilin.
There are also some neuron specific type IV filaments, like alpha-internexin, and a group simply called
neurofilaments which provide structural support for axons.
Finally, there’s type V and type VI intermediate filaments which are found in almost all of our cells: type V
intermediate filaments are lamins, which make up the nuclear lamina around the nucleus of a cell.
Then there are Type VI intermediate filaments which include nestin, which helps assemble and disassemble
other intermediate filaments.
Summary
Alright, as a quick recap, the cytoskeleton is formed by actin filaments, intermediate filaments, and
microtubules.
Actin filaments are the thinnest and help with muscle contraction, cell division, and even cell movement.
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Also, the response is really fast - occurring within minutes to hours, and there’s no memory associated with
innate responses.
Inflammation Generally speaking, there are two main types of leukocytes: granulocytes which include neutrophils, eosinophils,
basophils, and mast cells and agranulocytes which include lymphocytes and monocytes, which can differentiate
into macrophages or dendritic cells.
Inflammation classically describes four key signs - each of which have a latin derivation.
The inflammatory process usually begins with either macrophages or mast cells, both of which are found in the
Calor or heat, dolor or pain, rubor or redness, and tumor or swelling.
tissues.
Sometimes these four signs combine to cause a fifth sign, which is functio laesa or temporary loss of function
When there’s tissue damage, these cells respond to the PAMPs or DAMPs.
due to pain or swelling.
Mast cells have granules containing different inflammatory mediators like histamine, serotonin, cytokines, and
Okay - so inflammation usually starts with some stimuli, like a pathogen.
eicosanoids, such as prostaglandins and leukotrienes.
Now, even though pathogens are a common cause of infection which can lead to inflammation, inflammation
These inflammatory mediators act on the endothelial cells surrounding the capillaries nearby, causing them to
can be caused by other things as well like toxins and trauma.
separate from each other.
For example, after an intense workout, your muscles may feel sore - that's due to inflammation trying to repair
In addition, macrophages - which are the garbage truck of the body - begin to eat up invading pathogens.
your overused muscle fibers.
The release of cytokines causes capillaries to get larger, and increase vascular permeability, allowing plasma
Ultimately, the goal of inflammation is to respond to the stimuli and restore balance.
proteins and fluids to leave the circulation.
Oftentimes that includes eliminating the cause of tissue injury, clearing out necrotic or dead cells, and starting
Endothelial cells also help spur on this process by releasing nitric oxide, which helps vasodilate the capillaries
tissue repair.
and make them more permeable.
Broadly speaking, inflammation can be triggered by external and internal factors.
In addition, endothelial cells express more adhesion proteins to help leukocytes that are floating by in the blood
External factors can be non-microbial or microbial. Non-microbial factors include allergens, irritants, and toxic to attach and roll along the vessel wall until they reach the injured site.
compounds.
In particular, neutrophils get attracted to the site of infection by the chemokines and microbial products.
Now, the two main microbial factors that trigger inflammation are virulence factors and pathogen associated
The neutrophil then begins to squeeze through the gaps between two endothelial cells, until it reaches the other
molecular patterns or PAMPs.
side - this is called extravasation.
Virulence factors are molecules that help pathogens colonize tissues and cause infection.
It’s a bit like squeezing between two fence poles to sneak into an amusement park, rather than paying
PAMPs are small molecules with conserved patterns that are shared across many different pathogens, including admission. Not saying that you should do that.
bacterial wall components like peptidoglycan, lipopolysaccharide or LPS, and lipoteichoic acid, and fungal wall
Now next, the leukocyte follows a gradient of inflammatory mediators, to get to the site of inflammation.
components like mannan.
Neutrophils are the first leukocytes recruited during the acute inflammatory process, and they’re like hungry
For intracellular pathogens, like viruses, PAMPs might include the viral RNA or DNA.
athletes - they immediately start phagocytosing or eating pathogens and damaged cells.
Our immune system recognizes virulence factors and PAMPs as foreign substances, and can trigger an
Neutrophils take in a lot of pathogens quickly - like a vacuum - and then commit suicide - destroying themselves
inflammatory response against them.
and all of the pathogens they’ve taken in.
Now, in terms of internal factors, it turns out that there’s an endogenous equivalent to PAMPs, called damage
Now while this is all happening, there’s also a family of soluble proteins called the complement system.
associated molecular patterns or DAMPs.
The complement proteins most often get activated in the presence of antibodies bound to pathogens, or by
DAMPs are intracellular proteins that get released when a cell’s plasma membrane is injured or when a cell dies.
molecules on the pathogens.
So DAMPs are a signal that there’s serious cell damage and they trigger inflammation.
Once these complement proteins are active they help attract leukocytes, and help with opsonization, meaning
Now, PAMPs and DAMPs are recognized by Pattern Recognition Receptors or PRRs, which are cell surface that they can bind to microbes so that leukocytes can more easily phagocytose them - a bit like sticking a fork in
receptors on various leukocytes that help to activate those cells and spark the inflammatory response, which can a meatball so that it doesn’t slip away!
be thought of as the innate immune system.
Some of the complement proteins also kill pathogens by directly forming a channel in their membrane - literally
Key features are that this response is non-specific - meaning that PRRs don’t distinguish one specific pathogen punching a hole in it.
from another, although they can distinguish between broad categories like viruses from bacteria.
All the while, dendritic cells continue to phagocytose pathogens and present bits of them to T lymphocytes.
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This activates the adaptive immune system, which kicks in after a few days.
If the stimulus for all of this inflammation was a cut or scrape, then platelets and clotting factors from plasma
reach the area and clot the wound.
This helps stop the bleeding, prevents pathogens from entering the bloodstream, and provides a framework for
tissue repair.
In sum, all of these factors contribute to the heat, pain, redness, and swelling that’s classic for inflammation.
Now, the inflammatory response ends with tissue repair.
Macrophages are recruited to eat up dead and dying cells, so that the tissue can make room for new cells.
This is followed by angiogenesis, which is the formation of new blood vessels, and that’s triggered by growth
factors released by macrophages.
These newly formed blood vessels are temporary, meaning that once the wound has healed, these new vessels
regress.
Finally, there are fibroblasts, which come into the area of inflammation and synthesize collagen to help with
wound healing.
Overall, if there’s only mild damage, then the tissue regenerates back to its normal healthy state, but if there’s
severe damage, then the damaged cells get replaced by a non-functional fibrous scar.
Summary
Alright, as a quick recap, inflammation is a complex response to harmful stimuli which could be from a pathogen,
but also could be from trauma or toxins.
The response involves blood vessels dilating and becoming more permeable, and attracting more immune cells
and fluid into local tissue.
The classical signs of inflammation are heat, pain, redness, swelling and they can lead to a loss of function.
The inflammatory response ends with wound repair and resolution, either restoring the initial tissue integrity, or
leaving a fibrous scar.
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This whole example is very similar to Budd-chiari syndrome, where the hepatic veins that drain blood out
of the liver are blocked by a thrombosis, or a clot, and now blood can’t flow through the liver and the liver
tissue becomes ischemic and can lead to liver edema and hepatomegaly, or enlargement of the liver.
Ischemia
If the oxygen supply is low enough for long enough, it can cause cell death, and if enough cells die in a
region of tissue we would call that tissue necrosis and infarction.
Hypoxia, or lack of oxygen in cells and tissue, can happen in a number of ways, and ischemia's one of them.
In some cases, there are areas of tissue that are getting close to infarction, as cells begin to die off, but they
Ischo- means “restraint” or “suppression”, and -emia refers to the blood, so ischemia must mean some kind are still able to get saved if they receive blood.
of suppression or reduction of blood flow to an organ or tissue.
This high-risk area that’s teetering on the brink of death is called the ischemic penumbra.
And blood carries oxygen right? So when there’s a reduction in blood flow to cells, that also means there’s a
reduction of oxygen to those cells, and this is due to lowered blood flow in the blood vessels. In some cases, there are two arteries serving a single area of tissue.
This lowered flow could be from something blocking the blood from the inside, or it could be something And, this goes against how we often think about tissue as being served by a single capillary bed from a
compressing the blood vessel from the outside. single artery, but when you think about it in three-dimensions, there can be a lot of overlap.
An example of something blocking the blood vessel from the inside is a thrombus, also known as a blood If there are these secondary or collateral arteries going to the area then there might be enough blood flow
clot, these are solid clumps of platelets and fibrin that obstruct blood flow. to keep the penumbra alive for a while.
Ischemia resulting from something outside the blood vessel is traumatic injury, which can cause Over the course of weeks to months, these secondary arteries can even grow in size to bring through more
inflammation and swelling that physically applies external pressure to the blood vessel, compresses it, and blood to that area, a bit like disaster relief; this process is called collateralization.
restricts blood flow.
So if blood flow to an organ is blocked all of a sudden, a super important concept to keep in mind is called
Alright, so let’s say this is your artery, and it’s like the one-way highway leading all these red-blood-cells time to reperfusion.
into the city, which is like a major organ in the middle here, so maybe this is organ-apolis.
This refers to the importance of re-establishing perfusion to the affected organ before the cells die and the
These red blood cells are super pumped for their day where they can drive around the capillaries, like the ischemia becomes irreversible.
smaller city streets, and supply the city with fresh oxygen and pick up waste.
Remember that perfusion and blood flow are slightly different; blood flow is the volume of blood flowing
And this organ-apolis is made up of thousands of cells, like homes, that use up the oxygen and create waste per unit time, like L / min.
that needs to be picked up, the deoxygenated blood cells drain out through different small streets which are
the veins and go back towards the heart. Perfusion is like a measurement of how much blood is flowing to a chunk of tissue per time, so it might be
given in L per min per gram of tissue.
So one way this organ-city could become ischemic, is if there’s some obstruction to arterial flow into the
tissue. Now only a few red-blood-cells can get in at a time. So as an example, if you compared the total blood flow to the kidneys with the total blood flow to the liver,
it’d be higher to the liver because the liver’s a lot larger.
You might imagine that organ-apolis sees a lot less blood and a lot less oxygen, and becomes ischemic!
But if you took a 10 g cube of liver tissue and compared it to a 10 g cube of kidney tissue, the kidney
A super important and well-known example of this arterial ischemia is atherosclerosis, where plaque builds actually has higher perfusion, since it has more blood vessels packed into its cube.
up in the arteries going to your heart tissue, which blocks arterial flow, reduces the amount of blood and
oxygen that make it to your heart tissue, and causes ischemic heart disease. Now, back to reperfusion, if perfusion to the area is re-established quickly enough, then it’s possible that
the ischemia is reversible because the cells were dying but they’re not dead.
Since you can have a blockage of the red blood cells coming in, you can also have a blockage of red blood
cells going out, leading to a decrease in blood drainage on the venous side. If too much time has passed and the cells have actually died, then the ischemia is irreversible since you
can’t bring back dead cells.
So in this case, you’ve got a major obstruction in the venous highway leaving the city, so say these are like
the veins draining blood out of organ-apolis. One example of irreversible ischemic damage is something like a heart attack, or myocardial infarction,
where an artery supplying a specific part of the heart with blood becomes blocked, causing death of that
All these workers are getting into organ-apolis, but they can’t leave because there’s a blockage heading out, part.
and traffic gets majorly backed up, causing flow to slow down throughout the whole city!
Depending on the area that’s affected, this could cause serious heart dysfunction, like if enough of the
This again leads to less oxygen to the tissues and ischemia. heart’s ventricle was damaged, it might not be able to pump blood as well anymore.
Thinking about an organ, it might get so congested that pressure can rise causing fluid to get forced out of
the blood vessels and into the tissues generating edema.
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This process of producing superoxide ions and hydrogen peroxide is called the respiratory burst.
These ions and molecules destroy pathogens by breaking down their cell membranes and damaging their
Free radicals and cellular injury proteins.
Another way free radicals can be generated is through exposure to ionising radiations like ultraviolet light or X-
Electrons in an atom are present in spaces called orbitals, and each orbital can fit different pairs of electrons. rays.
Free radicals are molecules with an unpaired electron in their outer orbital. When the radiation hits the water in the tissues, it knocks off an electron.
Now, electrons don't like to be lonely so free radicals have a habit of stealing electrons from any molecule they So, if we go back to the previous sequence, and go backwards here from water, you’ll end up at the hydroxyl
come across to make themselves stable. radical.
This causes the victim molecules to be less stable which is why free radicals are a problem. Free radicals can also be generated when there’s a build up of metals like copper or iron in the body.
Now, a free radical is formed when any molecule gains or loses an electron. For example, hemochromatosis is a condition where unusually high amounts of iron is absorbed.
In the body, free radicals can be generated physiologically, which means as a part of the normal metabolic All this extra iron, undergoes the Fenton reaction, where molecules of iron 2+ are oxidized by hydrogen
processes; or pathologically, which is due to some disease. peroxide, producing iron 3+ and the hydroxyl radical and hydroxide ion as byproducts; now, iron 3+ can than be
reduced back to iron 2+ via hydrogen peroxide again, creating a peroxide radical and a proton, and then the
A major physiological source of free radicals is cellular respiration, which is also called oxidative phosphorylation.
cycle repeats, creating this like endless loop of free radical generation.
Oxidative phosphorylation is the body’s process of making ATP through the electron transport chain.
So, over time, all these deposits of iron slowly damage the cells in the various organs by free radical generation,
This chain is made up of electron carriers, called complexes, embedded within the inner mitochondrial that case cell death and then lead to tissue fibrosis.
membrane which pass electrons along like the baton in a relay race.
Free radicals are also produced following ischemia, or reduced of blood flow to an organ or tissue.
Together, they form the electron transport chain, which pass electrons from complex to complex.
At the cellular level, ischemic injury can lead to the production of ROS by the mitochondria.
The final step of this process involves a molecule called cytochrome c oxidase, sometimes known as complex IV,
If blood flow returns to the ischemic tissue, it's called reperfusion, which brings along with it more oxygen.
which transfers electrons to molecular oxygen, or simply O2, which then splits into two oxygen atoms.
Unfortunately, though, all this oxygen reacts with the ROS formed during ischemia to form more, which worsens
The transferred electrons make the oxygen atoms electronegative enough to grab two protons, or H+ ions, each
the cell damage, called reperfusion injury.
from the mitochondrial matrix - making two molecules of H20.
Finally, free radicals can also be generated when chemicals or medication that enter the body are being
Normally, four electrons are required to convert O2 into two molecules of water.
metabolised by the liver.
But when less than four electrons are transferred to oxygen, then it will have unpaired electrons in its orbitals,
For example, acetaminophen is an analgesic medication metabolised by the liver enzyme cytochrome P450.
giving rise to free radicals.
During this process though, free radicals like phenoxyl free radical and N-acetyl-p-benzoquinone imine can be
Since these are formed from oxygen, they’re collectively called reactive oxygen species, or simply ROS.
generated, and so when high doses of acetaminophen are taken, it can cause massive death of tissue in the liver,
Okay so if oxygen is given one electron, it becomes superoxide (so O2 with a little dot for its extra electron). and this is mainly from free radical damage.
If it gets two electrons, it becomes hydrogen peroxide, or H2O2, and then 3 electrons, it’s hydroxyl radical. Another example is the chemical carbon tetrachloride, or CCl4 which was used in the cleaning industry.
There are also pathological conditions where free radicals can be generated. When this guy enters the body, P450 enzyme converts it into trichloromethyl radical, or CCl3, which can again
cause damage to the liver.
First, they can be produced during an inflammation by phagocytes like macrophages and neutrophils.
Since the body generates free radicals even under normal conditions, there are certain defence mechanisms in
When a pathogen invades the body, the phagocyte gobbles up the pathogen forming a phagolysosome. place to keep them in check.
These phagocytes also have an enzyme called NADPH oxidase, which gets activated by the lysosomal enzymes, One of them is antioxidants like vitamin A, vitamin C, and vitamin E, which do the opposite of free radicals by
causing NADPH to undergo oxidation, and lose two of its electrons. donate electrons, and protect the cells.
Nearby oxygen molecules can grab these electrons to form superoxide ions, or O2- ions. There’s also another molecule in our body called glutathione which acts as an antioxidant and goes around and
neutralizes H2O2.
Another enzyme, superoxide dismutase, can take these ions and combine them with hydrogen ions to form
hydrogen peroxide, or H2O2.
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In order to function, glutathione needs to be in the reduced state where it can donate an electron to the H2O2
and convert them into harmless water and oxygen.
However this causes the glutathione to become oxidized, so before it can get back to work, an enzyme called
glutathione reductase will use an NADPH as an electron donor and and reduce the oxidized glutathione back into
its working state.
After giving up its electron, the NADPH will become NADP+.
So to replenish the supply of NADPH, we have the glucose-6-phosphate dehydrogenase enzyme, or G6PD, which
reduces NADP+ back to NADPH by oxidizing a glucose-6-phosphate.
Glucose-6-phosphate is a metabolite of glucose so we usually have a ready supply of this molecule as long as we
are not starving.
Another defence mechanism is metal carrier proteins which bind to the metal ions and help in transporting or
storing them.
This way the ions are sort of like hidden away and so, are not able to generate free radicals.
For example, transferrin which binds to iron, and ceruloplasmin which binds to copper.
And finally, there are also free radical scavenging enzymes which convert the free radicals into harmless
substances like water.
Superoxide dismutase, takes superoxide and converts it into hydrogen peroxide.
Catalase converts hydrogen peroxide into water in peroxisomes, and glutathione peroxidase does the same in
the cytoplasm.
When the amount of free radicals produced overwhelms the defence mechanisms, cell damage starts to occur.
Free radicals can react with the lipids in the cell membrane, causing lipid peroxidation.
For example, let’s say a hydroxyl radical has attacked this particular lipid molecule.
This molecule is now left with an unpaired electron, so it in turn grabs an electron from the next lipid molecule,
setting up a sort of chain reaction which ends up damaging the cell membrane.
Free radicals can also cause oxidative modification of proteins, which affects the function of enzymes and other
structural proteins.
Oxidation of DNA can cause breaks in the DNA strands, and can also introduce mutations which increase the risk
of cancer.
Summary All right, as a quick recap… Free radicals are chemical species with an unpaired electron, which can
damage the cells by oxidizing the lipids, proteins, and even the DNA.
They are produced in the body physiologically by the electron transport chain, and pathologically during
inflammation, exposure to ionizing radiation, metabolism of chemicals or medication like acetaminophen, build
up of metals like iron or copper, and reperfusion of ischemic tissue.
Free radicals are normally kept in check by antioxidants, metal carrier proteins and free radical scavenging
enzymes.
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As a result, the cell membrane starts to develop blebs - or bulges in the cell membrane.
The blebs are structurally weak, so they start to break off from the cell membrane, and this attracts nearby
Necrosis and apoptosis macrophages, which begin to clean up the mess by eating up the cell fragments.
So apoptosis is a neat process that conveniently recycles the organic contents of the dead cell.
Generally speaking, cells have two ways to die. One way is by apoptosis, which is a form of programmed cell
death - a bit like cellular suicide. Now, when the signals from apoptosis come from outside the cell - it’s called the extrinsic pathway.
The second way is by necrosis, which is when cells die due to injury or disease. One example is when a nearby macrophage recognizes an old cell, a pathogenic cell, or a cell that has completed
its task.
Overall, apoptosis occurs much more often than necrosis.
In these situations, a macrophage can initiate apoptosis by releasing tumor necrosis factor alpha or TNF-alpha, a
One example is when old skin cells undergo apoptosis, and get replaced by new skin cells. cell signaling protein, that binds to very appropriately named death receptors on the target cell membrane, one
example being tumor necrosis factor receptor 1.
Another example is in our hands and feet during fetal development.
The cytosolic end of this receptor, dives deep inside the cell, and it’s called the death domain.
Initially, human hands and feet look like duck's feet, with webs of skin connecting the fingers.
When the TNF-alpha binds to the tumor necrosis factor receptor 1, the death domain changes its shape and is
But the cells in the webbing undergo apoptosis and that allows us to form individual digits that allow us to pick
able to bind to two proteins.
our nose and play the piano.
One is called Fas-associated protein with death domain or FADD and the other is called take a deep breath here
In contrast, necrosis occurs less frequently, and an example of that is when a blood vessel that goes to your big
Tumor necrosis factor receptor type 1-associated DEATH domain protein or TRADD.
toe gets clogged causing ischemia, which is where oxygen and nutrients can’t reach the cells.
So the death receptor, FADD, and TRADD come together to form a multi-complex protein called... wait for it...
As a result, those cells begin to die, turning your big toe a nasty shade of black.
the death-inducing signaling complex or DISC.
In apoptosis, there are two activating mechanisms - the intrinsic pathway, also called the mitochondrial
Once everything is together, DISC cleaves pro-caspase-8 into caspase-8, which in turn activates caspase-3, and
pathway, and the extrinsic pathway, also called the death receptor pathway.
caspase-3 goes on to activate other caspases.
The intrinsic pathway occurs when a cell is exposed to stress like radiation, hypoxia, or low oxygen, a high
This initiates the caspase cascade that commits the cell to apoptosis.
intracellular concentration of calcium ions, or oxidative stress, which is where reactive molecules with unpaired
electrons called free radicals steal electrons from nearby molecules. After that, the process of apoptosis unfolds just like in the intrinsic pathway.
These stressors cause two intracellular proteins, Bax and Bak, to move from the cytosol to the mitochondria. Now in addition to macrophages, if a cytotoxic T cell detects that a cell is expressing foreign antigens, the T cell
will express a protein on its membrane called Fas ligand which binds to a death receptor on the target cell called
Once in the mitochondria, Bax and Bak pierce the outer mitochondrial membrane making it porous and leaky.
the first apoptosis signal receptor - or Fas receptor.
This allows two additional proteins, called SMACS and cytochrome C, to spill into the cytosol.
Similar to the death domain of tumor necrosis factor receptor 1, the Fas receptor protein also has its very own
SMACS binds to proteins that normally inhibit apoptosis and deactivates them. death domain that can bind to FADD to form DISC.
Meanwhile, cytochrome C binds to both ATP - the main form of intracellular energy - as well an enzyme called As before, DISC activates pro-caspase-8 into caspase-8 and that triggers the caspase cascade which leads to
Apaf-1. apoptosis.
Together, cytochrome C and Apaf-1 combine to form a large protein complex called an apoptosome. Now let’s switch gears and look at necrosis - which can be triggered by external factors like an infection or
extremely hot or cold temperatures, as well as internal factors like tissue ischemia.
The Apaf-1 portion of the apoptosome then cleaves an enzyme called pro-caspase 9 into its active form,
caspase-9. Necrosis can start one of two ways. The first is a form is called oncosis, which starts when toxins or ischemia
damage the mitochondria.
Caspase 9 then goes on to activate caspase-3, and caspase-3 goes on to activate other caspases - like a chain
event. If the mitochondria no longer synthesize ATP, everything stops working - including the ionic pumps that regulate
the flow of ions in and out of the cell.
Eventually this caspase cascade leads a cell to commit apoptosis.
Without functioning ion pumps, sodium starts to flow into the cell and its followed by water which causes the
That’s because these caspases cleave the proteins that make up the cell’s nucleus, organelles, and cytoskeleton - cell to swell up like a balloon.
a bit like a ninja sabotaging a bridge by removing its nuts and bolts.
Soon, the cell bursts and spills its internal contents on neighboring cells, and this attracts nearby immune cells
This destroys the cytoskeleton, as well as the proteins that anchor the cytoskeleton to the cell membrane. and triggers the inflammatory process.
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Immune cells release substances like proteases, which are enzymes that degrades proteins, and reactive oxygen The dead cells disintegrate but are not fully digested, which leaves the tissue with a cottage cheese consistency.
species - which are unstable and damage other cells.
Next, there’s fat necrosis, which most commonly occurs when there’s trauma to fatty organs that have a lot of
If this inflammatory process occurs among enough cells, it can destroy the tissue, and if it happens on a massive adipose cells, like the pancreas or the breasts.
level it can lead to organ dysfunction.
Trauma to the pancreas or the breasts ruptures the adipose cell membranes, which makes them spill their fatty
Now it turns out that cell necrosis comes in a few different flavors. acids into the extracellular space.
First, there’s coagulative necrosis, which occurs when a tissue becomes hypoxic - has low levels of oxygen - most There, the fatty acids combine with calcium, which leads to dystrophic calcifications in the tissue -that look like
commonly due to ischemia. bits of chalk in the tissue.
Hypoxia causes structural proteins to bend out of shape - like twisting a paperclip so that it can no longer work. Now, in addition, the pancreas can also undergo fat necrosis as a result of inflammation - called pancreatitis.
Hypoxia also affects lysosomal enzymes which become ineffective at getting rid of the affected proteins. With pancreatitis, the pancreatic cells spill lipase around the pancreas.
So although the cells die, they retain some structure and don’t get completely destroyed. Lipase helps digest fats, so it causes fatty acids to spill out of the fatty retroperitoneal tissue that’s adjacent to
the pancreas.
From a macroscopic level, the dead tissue becomes a gel-like substance, and has a pale wedge-shape, with the
apex oriented towards the obstruction. Finally, there’s fibrinoid necrosis which is almost always found in malignant hypertension and vasculitis.
That’s because a blood vessel typically serves a region of tissue that typically fans out, and all of that tissue With hypertension, a constant high blood pressure damages the muscular wall of the small arteries, so fibrin - a
becomes hypoxic and then undergoes coagulative necrosis. protein involved in the clotting of blood - starts to infiltrate and damage the walls of the damaged blood vessels.
Occasionally, blood re-enters the area of necrosed tissue, like if a blocked blood vessel opens back up - and Similarly, in vasculitis, there’s an inflammatory reaction in the blood vessel walls that causes destruction.
when that happens it gives the tissue a dark red color and it’s called a red infarct.
Coagulative necrosis can occur in any cell of the body, but it occurs most often when there’s low oxygen to Summary
heart, kidney, or spleen tissue.
Alright, as a quick recap, apoptosis is a commonly occurring form of programmed cell death, whereas necrosis is
Next, there’s liquefactive necrosis, and that occurs when hydrolytic enzymes completely digest the dead cells
a less common process where cells die due to injury or disease.
into a creamy substance full of dead immune cells - think of a cream filled donut.
Apoptosis occurs due to intrinsic and extrinsic pathways.
Liquefactive necrosis is most commonly seen in the brain, however, it can also happen to pancreatic cells, or
within an abscess located anywhere in the body. With apoptosis, white blood cells come in and clean up the dead tissue, so this is a neat way for cells to die.
The brain has resident macrophages called microglial cells that contain hydrolytic enzymes. Necrosis occurs because of external factors like an infection, as well as internal factors like tissue ischemia.
These enzymes completely destroy damaged brain cells - basically liquefying the dead brain tissue. There’s six types of necrosis: coagulative and gangrenous necrosis, which happen to hypoxic tissues; liquefactive
necrosis, which happens because of hydrolytic enzymes; caseous necrosis - like in tuberculosis; fat necrosis,
Similarly, the pancreas has various enzymes like trypsin that are designed to digest food, but sometimes get
which happens when fatty acids spill outside adipose cells, like during trauma, and finally fibrinoid necrosis -
activated in chronic inflammation due to gallstones or alcohol consumption, and destroy the pancreatic tissue
which is caused by fibrin deposits, like in malignant hypertension.
itself.
Finally, in abscesses, neutrophils use their proteolytic enzymes to liquify tissue - which results in pus.
Next, there’s gangrenous necrosis, and it also occurs due to hypoxia - so, that’s why some consider it a form of
coagulative necrosis.
Gangrenous necrosis typically affects the lower limbs and gastrointestinal tract, and it causes the tissue to get
dried up like a mummy - sometimes called dry gangrene.
But if the dry gangrene gets infected, then liquefactive necrosis can occur, and then it’s called wet gangrene.
Next, there’s caseous necrosis, and it’s a bit of a mix between coagulative and liquefactive necrosis.
Typically, it’s the result of a fungal or mycobacterial infection - classically Mycobacterium tuberculosis which
causes tuberculosis.
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The good news is that this type of muscle atrophy is reversible with exercise.
There’s also a more severe form of muscle atrophy which happens in cachexia - or whole body wasting
Atrophy, aplasia, and hypoplasia syndrome.
That form of muscle atrophy is often so severe that it’s not typically reversible and happens in severe
Growing is an important part of living. illnesses like AIDS, or in some forms of cancer patients.
In fact, everything from an individual muscle cell, to a baby blue whale - strives to grow, in order to live and But atrophy is not necessarily pathological - in fact, it’s often a part of normal development.
perhaps replicate or reproduce.
For example, it happens in the thymus.
Sometimes, however, growth fails to occur, or even reverts back, and we call that atrophy, aplasia, or
hypoplasia, depending on the situation. The thymus is a small organ that sits over the heart and is responsible for the maturation of T cells which
are part of the immune system.
Let's break down these words. Atrophy, “a” means “no”, and “trophy”, means nourishment. So, atrophy
means “no nourishment”. As children grow and their immune system gets established, the thymus begins to atrophy.
Aplasia, “a” means “no” and “plasia” means development. So aplasia means “no development”, and “hypo” This process is called thymus involution.
means “under” so hypoplasia is “under formation”.
As a result, the thymus is much larger in young children than it is in adults.
In a nutshell, atrophy is the reduction in size of a cell, organ, or tissue, after it has attained its normal,
matured growth. Now, aplasia and hypoplasia are somewhat different; they’re both ways in which growth can go wrong
during embryogenesis - when our organs develop within the fetus.
This happens either through decrease in cell number or decrease in cell size.
With aplasia, the precursor cells are completely absent, while in hypoplasia, there are some precursor cells
Decrease in cell number most commonly happens due to apoptosis, which is controlled type of cell death - a present, but not enough of them.
bit like cellular suicide.
With aplasia, the organ never forms in the first place- so this is the more severe case.
An example would be weight loss. In the first few weeks to months of eating healthy and losing weight, the
fat cells or adipocytes get smaller but are ready to fill up again with fat. Going back to the thymus again. In DiGeorge syndrome, a small part of the 22nd chromosome is deleted, so
the genes that code for the thymus are gone.
Over months to years of eating healthy, however, the adipocytes undergo apoptosis - and at that point it’s a
bit more difficult to gain back the weight. As a result the cells never have the DNA they need to express the proteins that would turn them into thymic
precursor cells.
Decrease in cell size, however, is a bit more complex.
As a result, the thymus never forms, and the person is left with a severely impaired immune system.
Usually, the first step is the loss of nerve or hormonal supply, both of which provide nourishment to cells.
Hypoplasia, or underdevelopment, is more common and usually results in milder consequences.
Then there’s something called the ubiquitin proteasome pathway.
Here there are only some precursor cells available, and that results in a smaller, or misshapen organ.
You see, cells have a cytoskeleton, which is a framework of various filaments that keep the cell propped up.
One example is a genetic disease called optic nerve hypoplasia, where there are fewer neurons than normal
As cells start getting less nourishment, those filaments get “tagged” for demolition with a protein called serving the eye.
ubiquitin.
As a result, the optic nerve is abnormally thin. The result can vary wildly - from near blindness, to near
Ubiquitin proteins start to attach to one another - a process known as polyubiquitination. normal eyesight, all depending on how many axons formed in the first place.
And then an intracellular protein complex called a proteasome comes in to destroy all polyubiquitinated
filaments, causing the cell to decrease in size.
Summary
Some organelles can also be tagged with ubiquitin; and when that happens, a bubble of phospholipid
bilayer membrane forms around the organelle, creating a vacuole.
Alright, as a quick recap - atrophy, aplasia, and hypoplasia are terms for lack or absence of growth in an
Next, lysosomal vesicles which are filled with degradative enzymes, fuse with the vacuole; destroying the organ or a tissue.
unfortunate organelle. Like being sent off to the firing squad.
Atrophy means the wasting of a previously normally mature organ or tissue, aplasia usually means a
An example is muscle atrophy. complete congenital lack of an organ or a tissue, while hypoplasia means a relative congenital lack of cells
in an organ or a tissue.
Anytime there’s long-standing disuse of muscles, like extended bedrest, zero gravity, or during long study
sessions, there can be a loss of muscle mass and strength.
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In dysplasia, the tissue develops a large number of immature cells that have weird shapes, which you don’t
typically expect in normal, healthy tissue.
Metaplasia and dysplasia There are four major pathological microscopic changes.
The first is cellular pleomorphism meaning that the cells are of uneven size - which is a strange finding,
Do you remember your first day in elementary school? Everything and everyone was new and nothing was since usually tissue contains cells that are of roughly the same size.
impossible.
Next there’s nuclear pleomorphism or variation in size and shape of the nucleus.
But as you went through your education, you got further and further differentiated from your original
classmates. There’s also hyperchromatism - which means that the cells have abnormal nuclear morphology due to
abundant nuclear chromatin, resulting in darkly staining nuclei.
That's analogous to what happens to a cell that undergoes cellular differentiation.
And finally, there can be an increased number of cells with mitotic figures - meaning that a lot of cells are
An undifferentiated stem cell can become pretty much any tissue, influenced by both genes and the undergoing mitosis, or cell division.
environment.
All of these are signs of unhealthy cells that may be cancerous.
Now sometimes, environmental stresses can alter that developmental path.
Let’s take the example of the cervix, which is normally lined with glandular epithelium.
In metaplasia what happens is that a mature, differentiated cell type is replaced by another mature,
differentiated cell type. However, infection with certain strains of human papillomavirus, or HPV, can cause the cells to become
dysplastic.
Often, this happens because there’s an environmental stressor, that the new cell type is better suited to
handle. They can resemble immature squamous, epithelial cells, of various sizes and shapes, and they multiply at a
faster rate than normal cells would.
One example, is switching from breathing clean air to inhaling tobacco smoke each day.
Uncontrolled multiplication is generally bad news, therefore, dysplasia is considered a precancerous state.
Our airways are lined with columnar respiratory epithelial cells, which generally work well with air
breathing, but not so well when faced with an irritant, such as tobacco smoke. As they multiply further, we begin to speak of carcinoma in situ - which is a localized cancer.
In response to the toxins in the smoke, already differentiated, mature columnar respiratory epithelial cells Sometimes these immature and abnormal cells start to multiply so much that they break through the
are replaced by stem cells undergoing differentiation into sandbag-shaped squamous epithelial cells, which basement membrane.
become stratified - meaning that they form layers on top of another.
The basement membrane is a layer of fibrous tissue that separates epithelial tissue from underlying tissues.
This replacement of already differentiated, mature cells into another type of cell is known as metaplasia.
So if the cells break through that barrier and continue multiplying, they can begin exerting pressure on
Another example is our esophagus, which is lined with a nonkeratinizing squamous epithelium. local tissues, and break off clumps of cells that can go off to other tissues to spread the problem.
These cells are adapted to withstand the passage of food going down to our stomach. At this point it’s considered an invasive, cervical carcinoma.
However, in case of gastroesophageal reflux disease, acid from the stomach makes its way up into the
esophagus on a regular basis.
Summary
Esophagus cells are not well-suited for chronic contact with acid and can get damaged.
Normally, when there’s occasional damage, stem cells differentiate into new squamous epithelial cells to Alright, as a quick recap. Metaplasia and dysplasia typically result from chronic environmental stressors.
replace the damaged ones.
Metaplasia is the replacement of one mature type of cells into another mature type of cells, while dysplasia
But when there’s regular exposure to acid, stem cells begin to adapt by differentiating into nonciliated, is an increased amount of immature cell types, which may sometimes show unusual properties as well.
mucin producing columnar epithelial cells.
Metaplasia is generally benign, while dysplasia is considered a precancerous state, that can develop into
These cells are far better suited to withstand the acid - after all, they’re the same types of cells that are carcinoma.
found in the small intestine.
This is an example of metaplasia, and the condition is known as Barrett’s esophagus.
Now, metaplasia is technically reversible - so if the gastroesophageal reflux disease is treated, stem cells
will begin to divide into regular esophagus epithelial cells again.
On the other hand, if the problem persists, the cells can become dysplastic.
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In preparation for breastfeeding, hormones like prolactin, progesterone, and human placental lactogen
stimulate the growth of glandular tissue in the breast causing them to enlarge.
Hyperplasia and hypertrophy An example of pathologic hyperplasia is having excessive hormonal stimulation.
For example, normally, during a menstrual cycle, the endometrium, which forms the inner lining of the
Imagine a lumberjack. At first she can handle cutting down a few trees a day, but suddenly her boss wants uterus, grows and proliferates when exposed to estrogen.
her to chop down an entire forest by the end of the week! Now she's stressed out from the increased
demand! But if there is an overproduction of estrogen by an ovarian tumor, it can lead to excessive endometrial
growth - also called endometrial hyperplasia.
Our body is the same; when the demand placed on an organ or tissue is more than it can handle, its called
“stress,” and the body can adapt through either hyperplasia or hypertrophy. Now, one problem with hyperplasia is that it’s sometimes associated with cancer.
Hyperplasia refers to the process where cells in an organ or tissue increase in number, so its like hiring a Normally, hyperplasia is an adaptive response to stress, so it’s a tightly regulated process, meaning the
bigger pack of lumberjacks. tissue doesn’t grow out of control.
Hypertrophy is when these cells in an organ or tissue increase in size, like if the lumberjack gets really And in hyperplasia the process stops if the stress factors are eliminated.
tough so that she can cut down twice as many trees.
That’s different from cancer where there’s uncontrolled cell division.
So hyperplasia, bigger pack, and hypertrophy, tough lumberjack!
Now, the thing is that as cells divide in hyperplasia some can mutate and that’s how hyperplasia can slip
So, a tissue or organ might get stressed by physiological processes or from disease processes. into dysplasia and eventually into malignancy.
An example of physiologic hypertrophy is lifting a 10 pound sack of potatoes which puts a bigger functional While cells from hyperplasia are normal and healthy, cells from dysplasia can have an abnormal shape and
demand on your skeletal muscles. function.
In response, the muscle cells produce more proteins or myofilaments and get larger in size, allowing the And malignant cells might not only be abnormal, but also replicate uncontrollably, causing cancer.
biceps as a whole to generate more force. As a result your muscles also become bigger and tougher.
And that’s why individuals with endometrial hyperplasia that’s left untreated, can develop endometrial
An example of pathologic hypertrophy is when the heart undergoes hypertrophy to deal with high blood cancer.
pressure or hypertension.
Finally, it’s important to remember that in tissues that have stem cells, hyperplasia and hypertrophy
In hypertension, the heart has to pump blood against a high resistance and cardiac myocytes once again usually occur together when there’s increased stress.
adapt by increasing the synthesis of myofilaments causing individual cells to get bigger.
For example, in pregnancy, the uterus gets stimulated by estrogen, which lead to hypertrophy and
In both cases there’s hypertrophy, but the triggers are quite different. hyperplasia of the smooth muscle cells in the uterine wall. Meaning that the cells get tougher and the pack
of cells gets more numerous.
Now, in hyperplasia there’s an increase in the number of cells - a larger pack.
And that can only happen in organs with stem cells that can undergo cellular differentiation to become a
mature cell in that organ, like cells in the intestines for example.
Summary
So hyperplasia doesn’t occur in relatively permanent tissues without stem cells- like cardiac, nerve, and
adult skeletal muscle tissue. Alright, as a quick recap, whenever an organ encounters any sort of physiological or pathological stress, it
adapts by hyperplasia or hypertrophy.
And that’s why those tissues typically only undergo hypertrophy when they face increased stress.
You can remember that as - hyperplasia, bigger pack, and hypertrophy, tough lumberjack!
Now there’s compensatory hyperplasia and hormonal hyperplasia.
In general, hyperplasia and hypertrophy occur together in organs with stem cells like the skin, liver, bone
Compensatory hyperplasia occurs in organs that regenerate, like the skin, lining of the intestines, the liver,
marrow or uterus.
and bone marrow.
Organs that lack stem cell like the heart, skeletal muscle, and nerve can only undergo hypertrophy.
Hormonal hyperplasia occurs in organs that are regulated by hormones like organs in the endocrine and
reproductive system.
Like hypertrophy, hyperplasia can also be physiological or pathological.
An example of physiologic hyperplasia is enlargement of the female breast during pregnancy.
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And these cyclin dependent kinases are, as you might guess, dependent on cyclin proteins.
So what happens is that when there’s DNA damage, the cell doesn’t produce cyclins, the cyclin dependent
Oncogenes and tumor suppressor genes kinases can’t phosphorylate proteins within the cell, and that’s the signal for the cell to halt the cell cycle.
Okay, so proto-oncogenes code for proteins involved in promoting the progression of the cell-cycle.
Oncogenes and tumor suppressor genes are classes of genes that code for various proteins that are involved in
the progression of the cell cycle. Examples of proto-oncogenes include genes that code for growth factors or growth factor receptors - like the
receptor tyrosine kinase or RTK which adds phosphate groups to other proteins.
Oncogenes are actually mutated versions of proto-oncogenes, which are normal genes in charge of positive
regulation of the cell-cycle. Another example are genes that code for signal transduction proteins - like Ras genes, that code for Ras
proteins.
So the protein products of proto-oncogenes stimulate cell growth and division - they're like a gas pedal in a car.
Ras proteins are GTP-ases, meaning that they bind an intracellular GTP molecule, and break it down into GDP
Tumor suppressor genes, on the other hand, are in charge of negative regulation of the cell cycle, so their and a free phosphate group.
protein products stop its progression and promote apoptosis or cell death.
This further activates various cellular pathways, which ultimately result in cell growth, differentiation, and
Tumor suppressor genes are involved in DNA repair mechanisms and inhibiting transcription factors that try to survival.
push the cell along in the cell cycle - so they’re like the brake pedal in a car.
Another example is the MYC proto-oncogene which codes for a transcription factor that increases expression of
Now, the cell cycle is the series of events that a cell goes through as it changes from being one cell into two cyclins and cyclin dependent kinases.
daughter cells.
On the other hand, there are also proto-oncogenes that code for proteins that inhibit apoptosis.
The cell cycle has two phases: interphase and mitosis. Interphase is comprised of the G1 phase, during which the
cell grows and performs its cell functions, the S phase, during which DNA is replicated, and the G2 phase, during An example is bcl-2 which prevents the activation of caspases - the enzymes that actually carries out apoptosis.
which the cell grows again before entering mitosis.
Now, proto-oncogenes are normally only active when a cell needs to grow and divide - like you only push the
At the end of G1 and G2, there are cell cycle control points called the G1 and G2 checkpoints, where the cell accelerator pedal in a car when you want to speed up.
checks to see if there’s any DNA damage.
However, some genetic mutations like translocations, amplifications, or point mutations turn proto-oncogenes
The main control point is the G1 checkpoint. into oncogenes.
If it turns out that there is DNA damage, then the cell can either enter a non-dividing state called the G0 phase, When a gene is an oncogene it gets overexpressed - meaning, it results in too many proteins, or it means that it
where the DNA repair mechanisms try to fix the problem, or the cell can self-destruct in a process called codes for hyperactive proteins - which would be kinda like leaving a brick on the gas pedal and going to take a
apoptosis. nap in the backseat as the car speeds down the highway.
Now, if the cell does get the go-ahead at the G1 checkpoint, it enters the S phase. Cells have two copies of proto-oncogenes; however, if there’s a dominant mutation, that means that just one
mutant oncogene copy is enough for the cell to avoid apoptosis and keep growing and dividing uncontrollably.
And then if the cell gets past the G2 checkpoint, it enters mitosis, and it divides in two identical daughter cells.
One example is a type of B cell lymphoma called Burkitt lymphoma, which can result from a chromosomal
However, once cells differentiate and become mature cells - like liver cells for example - they don’t necessarily translocation.
go through the cell cycle over and over again.
When that happens the Myc gene is translocated from chromosome 8 to a spot where it’s right next to the IgH
Actually, cells tend to stay in that G0 phase, and some cells, like neurons, stay in G0 their entire life. promoter on chromosome 14 which upregulates - or stimulates - its expression.
Most other cells, however, stay in G0 until they get an external signal like a growth factor. The Myc protein then induces overexpression of cyclins and cyclin dependent kinases - which leads to
uncontrolled cell growth - a lymphoma.
These growth factors can be secreted by other cells, or by the cell itself, like when there’s a tissue injury, and the
remaining cells need to divide to replace the lost cells. Other oncogenes can result from a fusion gene.
Growth factors bind to growth factor receptors in the cell’s membrane, which activates signal transduction For example, the most common cause of chronic myeloid leukemia is a chromosome translocation which results
proteins. in a Philadelphia chromosome.
Ultimately that leads to increased transcription of genes that code for special proteins - like cyclins and cyclin A Philadelphia chromosome is one where a portion of chromosome 9’s long arm switches with a portion of
dependent kinases - so more of these proteins are being made. chromosome 22’s long arm.
This is important because whether or not a cell gets cleared at G1 and G2, depends largely on the activity of The result is two chromosomes - 9 and 22 - each of which have a bit of one another, and it’s chromosome 22
cyclin dependent kinases, which add phosphate groups to various proteins within the cell. with a bit of chromosome 9, that’s called the Philadelphia chromosome.
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So, in the Philadelphia chromosome, a chromosome 22 gene, called BCR, ends up sitting right next to a P53 binds to DNA and promotes transcription of a gene encoding protein called p21. p21 binds and inhibits the
chromosome 9 gene, called ABL. cyclin E-cyclin dependent kinase-2 protein complex, thus preventing passage from the G1 phase to S phase.
When they’re combined it forms a fusion gene called the BCR-ABL gene, which codes for a protein also called This buys a bit of time for DNA repair proteins, which are also expressed thanks to p53 - to get to work.
BCR ABL which is always getting expressed.
It turns out that P53 is a big deal in the molecular world, and was actually crowned “molecule of the year”, back
Now it turns out that BCR ABL has tyrosine kinase activity, meaning that it works as an on-off switch for various in 1993!
cellular functions, including cell division.
In fact, studies have found that more than 70% of human cancers are associated with mutations in the p53 gene.
Now because the BCR ABL gene is always getting expressed, the result is that myeloid cells keep dividing.
When mutations inactivate p53, the cell can no longer repair DNA before it enters the S phase, which means
This causes a buildup of premature leukocytes in the bone marrow, which eventually spill into the blood - mutations build up, and this can lead to uncontrolled cell division.
ultimately leading to leukemia!
Now, let’s switch gears to see how tumor suppressor genes work. Tumor suppressor genes code for proteins Summary
that stop the cell cycle or promote apoptosis - so they’re the cell cycle’s very own brake pedal.
Alright, as a quick recap, oncogenes are actually mutated versions of proto-oncogenes, which are normal genes
Like proto-oncogenes, tumor suppressor genes are also normally active throughout the cell cycle, and they code
that act like the accelerator pedal on the cell cycle - so they stimulate cell growth and division.
for proteins that halt its progression if there’s any sort of DNA damage.
Their protein products are growth factors, growth factor receptors, signal transduction proteins, transcription
Some genetic mutations - mainly deletions - turn off the expression of tumor suppressor genes - which leads to a
factors, and apoptosis regulators.
reduction in the number or function of the protein that they encode.
Tumor suppressor genes are like the brake pedals on the cell cycle - they inhibit progression to mitosis and/or
This is a recessive kind of mutation, because it takes two damaged copies for tumor suppressor genes to have no
promote apoptosis.
functioning proteins.
They include governor and guardian proteins like Rb and p53.
When that happens, it’s relatively easy for genetic mutations to accumulate, ultimately allowing the cell to keep
growing and dividing uncontrollably.
That’s why a wide variety of cancers feature mutated tumor suppressor genes.
For example, the Rb protein is considered a “governor” protein, because it normally inhibits cell proliferation by
binding and inactivating a transcription factor called E2F.
Normally, E2F promotes transcription of cyclin E, and cyclin dependent kinase-2, but it can’t do that with Rb
holding on to it for dear life.
But, here’s the catch - the Rb protein is only active and clinging to E2F when it isn’t bound to a phosphate.
So when a growth factor stimulates a growth signaling pathway, that activates the cyclin dependent kinases
which add a phosphate group to Rb, inhibiting it.
Phosphorylated Rb releases E2F, allowing the cell cycle to progress.
It’s like bribing the inspector with a phosphate to let the cell keep moving ahead with it’s plans.
In many types of cancer, including retinoblastoma - which gives Rb its name, Rb is inactivated and the loss of the
brakes increases the rate of cell division.
Typically, Rb is inactivated by a gene mutation, or by other proteins that specifically inactivate the Rb protein -
like protein E7 made by human papillomavirus.
Another example, is the p53 “guardian” protein. P53 is a transcription factor that checks for DNA damage before
a cell enters the S phase.
And if there is DNA damage, then specific protein kinases add phosphate groups to p53 - prolonging its life.
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Cell Pysiology

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Cell Physiology- Cellular structures and processes/ Cellular pathology

These processes require O2, so this is termed aerobic respiration.

The byproducts of this set of reactions are CO2 and H2O.

Now, this receptor also functions as a tyrosine kinase.

Type II is in our cool Cartilage.

Both endocytosis and exocytosis require ATP to happen.

It can be thought of as passive diffusion of water and it requires no energy.

G proteins bind to guanosine diphosphate or GDP when they’re inactive.

Another muscle-specific type IV intermediate protein is syncoilin.

Now, the inflammatory response ends with tissue repair.

After giving up its electron, the NADPH will become NADP+.

Superoxide dismutase, takes superoxide and converts it into hydrogen peroxide.

This is an example of metaplasia, and the condition is known as Barrett’s esophagus.

Like hypertrophy, hyperplasia can also be physiological or pathological.

An example of physiologic hyperplasia is enlargement of the female breast during pregnancy.

Phosphorylated Rb releases E2F, allowing the cell cycle to progress.

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