HORMONES

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HORMONES

The living body possesses a remarkable communication system to coordinate its biological functions.
This is achieved by two distinctly organized functional systems.

• The nervous system coordinates the body functions through the transmission of electrochemical
impulses.
• The endocrine system acts through a wide range of chemical messengers known as hormones.
Hormones are the chemical messengers of the body having diverse structures and functions. They act
either directly or through messengers to coordinate and perform biological functions such as growth,
reproduction and digestion etc.
❖ Hormones are defined as organic substances, produced in small amounts by specific tissues
(endocrine glands), secreted into the blood stream to control the metabolic and biological
activities in the target cells.
❖ Hormones may be regarded as the chemical messengers involved in the transmission of
information from one tissue to another and from cell to cell.
❖ The word hormone is of Greek origin, which means “to arouse to activity
some hormones can act on the adjacent cells in a given tissue (paracrine function) as well as on the cells
in which they are synthesized (autocrine function). Examples: interleukin-2 is autocrine hormone for it
is being produced by T cells and stimulates proliferation of T cells; and prostaglandins have paracrine
function since they act on nearby cells.

Chemical Diversity of Hormones


Based on their chemical nature, the hormones have been categorized into the following four groups:

1. Lipid hormones: Most lipid hormones are derived from cholesterol, such as adrenocortical
hormones, sex hormones and calcitriol. Others are derived from arachidonic acid, such as
prostaglandins. The cholesterol-derived hormones contain a steroid nucleus and are lipophilic
in nature; they readily traverse the cell membrane of their target cells and interact with the
cytoplasmic receptors.
2. Amino acid hormones: These hormones are produced by enzymatic modification of an amino
acid molecule. For example, both epinephrine and thyroxine are derived from tyrosine
molecule.
3. Peptide and protein hormones: These hormones are made up of amino acids, joined by
peptide bonds. Smallest of them is thyrotropin releasing hormone (TRH), a hypothalamic-
releasing factor, which consists of only three amino acids. Other examples include antidiuretic
hormone (9 amino acids), glucagon (29 amino acids), parathormone (84 amino acids), and
growth hormone (191 amino acids).
4. Glycoprotein hormones: A glycoprotein hormone consists of peptide chain to which
carbohydrate moieties are covalently attached. The latter are necessary for the biological
activity of these hormones. Examples include pituitary hormones (TSH, LH and FSH), and
chorionic gonadotropin (hCG) of placental origin.

Biosynthesis
Biosynthetic mechanisms for hormones are diverse. Some hormones are initially synthesized as large
precursor proteins which are converted to the biologically active forms by removal of specific peptide
sequences. Insulin, for example, is initially synthesized as an inactive precursor, pre-pro-insulin. A
sequential removal of two peptide sequences results in production of an insulin molecule. Likewise,
parathormone (PTH) is formed from precursor, pre-pro-parathormone by successive removal of two
peptide segments. thyroxine, a single amino acid hormone, which is processed from a 115 amino acid
glycoprotein precursor, thyroglobulin.

Transport
The peptide hormones circulate in the blood in free form, unbound to any transport protein. This is due
to their hydrophilic nature. In contrast, the steroid hormones and the thyroid hormones are
predominantly hydrophobic in nature and therefore, cannot circulate in blood entirely in an unbound
form. They are mostly transported to their site of action by carrier proteins

Target Tissue Concept


The physiological and biochemical effects of a given hormone are elicited only in a specific tissue,
known as its target tissue. A target tissue has specific receptors with which the hormone interacts. The
hormone-receptor interaction triggers a series of events that subsequently lead to biological effects of
the hormone.
For example:
Target tissue for thyroid-stimulating hormone (TSH) is the thyroid gland, where this hormone
stimulates synthesis and secretion of the iodothyronines (T3 and T4).
Adrenal cortex, the target tissue for ACTH, responds to ACTH by increasing steroidogenesis.
Other hormones (e.g. insulin, growth hormone, and cortisol) have more than one target tissues,
including liver, muscle and adipose tissue, where they influence a variety of metabolic processes.

Hormone Receptors
Receptors are cell-associated recognition molecules that play a crucial role in the hormone action.

❖ The receptors for water-soluble hormones (peptides, proteins, or glycoproteins) are present on
the cell surface. Interaction of hormones with receptors stimulates certain molecules namely
second messengers, which mediate biochemical functions intracellularly.
❖ The receptors for lipophilic hormones such as the steroids and the thyroid hormones are located
intracellularly.
The lipophilic hormones readily traverse the cell membrane because of their hydrophobic nature and
enter the cell. Intracellularly, they interact with specific receptors located either in the cytosol (e.g.
steroid hormones) or within the nucleus (e.g. thyroid hormones) to form hormone-receptor complexes.
The latter serves as the intracellular messengers, through which biochemical functions are mediated.
Thousands of receptor molecules may be present in a single cell.

Classification Based On Mechanism Of Action Of Hormones


Hormones have been classified in two major groups based on their mechanisms of action. The
mechanism of action depends upon the location of the hormone receptor and the nature of the signal
transmitted following the hormone-receptor interaction.
Group I
This group comprises the lipophilic hormones that are derived from cholesterol and the thyroid
hormones (exceptions—T3 and T4 ). These hormones interact with cytoplasmic or nuclear receptors
respectively. The hormone receptor complex itself acts as an intracellular messenger and directly
influences the gene expression
Group II
This group comprises the peptide, protein, and glycoprotein hormones. These hormones bind with the
surface receptors, located on the plasma membrane of the target cells. The hormone-receptor interaction
transmits a signal across the membrane, that results in elevation of the intracellular level of an
intermediary molecule, the so called second messenger (the hormone itself is the first messenger). The
second messenger acts as a signal-conducting molecule, through which the biological effects of a
hormone are mediated.
Depending on the chemical nature of the second messenger generated, group II hormones are further
divided into three subgroups (IIa, IIb and IIc):
Group IIa hormones employ cAMP as the second messenger. The second messenger for the group IIb
hormones is cGMP and those for the group IIc hormones is calcium or phosphatidylinositides (or both).
Hormones of group IId employ some multistep phosphorylation cascade that has not been fully
identified/settled.
Some hormones use different secondary messengers in different tissues. Action of PTH, for example,
is mediated via cAMP in renal cells and phosphoinositide/Ca2in bone cells. Likewise, vasopressin also
employs two different messengers in renal cells and muscle

Mechanism of Action of Group I Hormones


Sterol-derived hormones of this subgroup readily diffuse through plasma membrane of the target cells
and encounter specific, high-affinity cytosolic receptors. Formation of hormone-receptor complex is
followed by change in its conformation and surface charge, which results in activation of the complex.
The activated hormone-receptor complex is able to selectively bind specific regions of DNA (called
hormone responsive elements) and enhance transcription of specific genes. It is believed that the
interaction of hormone receptor complex with HRE promotes initiation and, to a lesser extent,
elongation and termination of RNA synthesis (transcription). The ultimate outcome is the production of
specific proteins (translation) in response to hormonal action.
Mechanism of Action of Group II Hormones
Hormones of this group are considered first messengers, and their intracellular effects are elicited
through mediator molecules termed second messengers. The hormones bind with cell surface receptors,
which are integral membrane glycoproteins, having three functional domains:
1. The extracellular domain that binds the hormone.
2. One or more transmembrane α-helices that penetrate the lipid bilayer.
3. Intracellular domain that is coupled with an effector mechanism.
The hormone receptor interaction transmits signal across the cell membrane to target proteins by the
following sequence of events
1. Binding of hormone with the extracellular domain of the receptor induces conformational
changes in the receptor.
2. These changes are transmitted to the transmembrane α- helices, from where they reach the
intracellular domain, which is associated with a guanine nucleotide-binding regulatory protein
or G-protein. It is a trimeric complex of three subunits (α βand ᵞ) associated with GDP in its
inactivated state.
3. The conformational change in the intracellular domain of the receptor activates G protein. The
activation involves GDP-GTP exchange, and dissociation of G-proteins into β ᵞand α -GTP
subunits.
4. Both these products bind to target proteins in plasma membrane, called effectors.
The best known effectors are second messenger synthesizing enzymes, such as adenylate cyclase, and
phospholipase C, guanylate cyclase, etc. These enzymes, when activated, generate second messengers
which serve as mediators of the hormone action. The commonest second messengers are:
1. Cyclic AMP (cAMP)
2. Phosphatidylinositides/calcium system
3. cGMP
Cyclic AMP (cAMP) is a ubiquitous nucleotide. It consists of adenine, ribose and a phosphate. cAMP
acts as a second messenger for a majority of polypeptide hormones. The membrane-bound enzyme
adenylate cyclase converts ATP to cyclic AMP. cAMP is hydrolysed by phosphodiesterase .
• Adenylate cyclase system
A series of events occur at the membrane level that influence the activity of adenylate cyclase leading
to the synthesis of cAMP. This process is mediated by G-proteins, so designed due to their ability to
bind to guanine nucleotides.
• Action of cAMP
Once produced, cAMP performs its role as a second messenger in eliciting biochemical responses.
cAMP activates protein kinase A (PKA). This enzyme is a hetrotetramer consisting of 2 regulatory
subunits (R) and 2 catalytic subunits (C). cAMP binds to inactive protein kinase and causes the
dissociation of R and C subunits.
4cAMP + R2C2→ R2(4cAMP) + 2C
(interactive) (interactive) (active)
The active subunit (C) catalyses phosphorylation of proteins (transfer of phosphate group to serine and
threonine residues). It is the phosphoprotein that ultimately causes the biochemical response. It should,
however, be remembered that cAMP does not act on all protein kinases. For instance, on protein kinase
C (the second messenger is diacylglycerol).
Dephosphorylation of proteins: A group of enzymes called protein phosphatases hydrolyse and remove
the phosphate group added to proteins.
cGMP as Second Messenger (Group IIb Hormones)
cGMP is an important intracellular messenger in retinal cells and some non-retinal cells. Steps involved
in the synthesis and degradation resemble the corresponding steps of cAMP. It is generated from GTP
by the enzyme guanylate cyclase (GC), and degraded by the enzyme phosphodiesterase (PDE), which
terminates its action.
Phosphatidylinositides/Calcium System as Second Messenger (Group IIc Hormones)
This system generates two intracellular second messengers: inositol 1,4,5-triphosphate (IP3 ) and
diacylglycerol (DAG) The hormones of group IIc bind to a cell-surface receptor, and the receptor
hormone complex activates a G-protein. The latter activates a membrane bound enzyme phospholipase
C (PLC), which acts on a variety of substrates, present on the inner plasma membrane. Phosphatidyl
inositol 4,5-bisphosphate (PIP2) is the most important of such substrates because its cleavage forms
two intracellular messengers, IP3 and DAG.

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