NEUROTRANSMITTER

Abdul Salam M Sofro Fakultas Kedokteran & LPPM Universitas YARSI

Neurotransmission
Intercellular communication is of vital importance. This holds in particular for the nervous system, since the nervous system is the main coordinating system in animals.

Nerve cells communicate with each other and with target cells by transmitting electrical signals and by releasing chemical messengers. Nerve cells contain one or more synapses, specialized structures essential for intercellular communication.

What is neurotransmitter ?
A neurotransmitter is a type of molecule that carries signals between neurons (nerve cells) at synapses in the nervous system.

At the left is the end foot (terminal bouton) of the presynaptic neuron. In the end foot you can see the synaptic vesicles containing molecules of neurotransmitter. The presynaptic neuron is separated from the postsynaptic neuron at right by the small gap called the synaptic cleft.

The synaptic vesicles and neurotransmitter molecules are highlighted. All the vesicles in a single axon's end feet contain molecules of the same neurotransmitter.

Neurotransmitters may be either excitatory (EPSPs) or inhibitory (IPSPs)

Excitatory Post Synaptic Potential is generally abbreviated to EPSP (fosters the initiation of a nerve impulse in the receiving neuron) Inhibitory Post Synaptic Potential is generally abbreviated to IPSP (inhibit the initiation of a nerve impulse in the receiving neuron)

 Synapses link the presynaptic, information transmitting nerve cells to the postsynaptic, information receiving cells. There are two types of synapses: electrical synapses and the more common chemical synapses. At a chemical synapse, the pre- and post-synaptic cell are separated by the synaptic cleft. The presynaptic cell contains vesicles filled with neurotransmitter molecules

 Upon stimulation of the presynaptic cell these vesicles are emptied in the synaptic cleft, a process called exocytosis. The neurotransmitter molecules diffuse the short distance across the synaptic cleft and reach the postsynaptic membrane. The neurotransmitters bind to postsynaptic receptors and trigger the postsynaptic respons. Thus, intercellular communication is initiated by the release of neurotransmitters from the presynaptic nerve cell.

Synaptic Transmission
1. structure of synapses 2. synthesis, packaging and transport of neurotransmitter molecules 3. release of neurotransmitter molecules 4. the activation of receptors by neurotransmitter molecules 5. reuptake, enzymatic degradation and recycling of neurotransmitters

The Synapse
axodendritic synapse (as in figure) axosomatic synapse (synapses of terminal buttons on somas cell bodies) dendro-dendritic (either direction) axoaxonal (e.g. presynaptic inhibition)

Directed vs non-directed synapses

fig. 4.9

fig. 4.11

Exocytosis
process of Neuro-transmitter release when AP arrives, Ca+ channels open influx of Ca+ causes vesicles to fuse with presynaptic membrane & empty contents into synaptic cleft small-molecule neurotransmitters: released in bursts peptides: released gradually

Activation of Receptors
neurotransmitters produce signals in postsynaptic neurons by binding to receptors in postsynaptic membrane each receptor only accepts a certain neurotransmitter one neurotransmitter may bind to different receptors (receptor subtypes )

Activation of Receptors (cont.)

neurotransmitter binding affects postsynaptic neuron in one of 2 ways: 1. ionotropic receptors ligand-activated ion channels very fast EPSPs or IPSPs 2. metabotropic receptors signal proteins & G proteins (guanosinetriphosphate-sensitive proteins) effects are slower to develop & more long lasting

fig. 4.13

Second Messenger
synthesized as a result of a G-protein subunit breaking off into the neuron diffuses through cytoplasm of cell has potentially long -lasting effects: 1. binds to ion channels (producing EPSPs or IPSPs), or 2. influences metabolic activities of cell, or 3. enters nucleus and binds to DNA, influencing gene expression

Autoreceptors
metabotropic receptors bind to their neurons own neurotransmitter molecules located on the presynaptic membrane function to monitor # of neurotransmitter molecules in synapse reduce subsequent release when levels are high increase release when levels are low

Pre-synaptic actions Places a drug can act prior to the release of a neurotransmitter
A. Disrupt the synthesis of neurotransmitter B. Disrupt the transport of neurotransmitter to axon terminal C. Affect storage of the neurotransmitter D. Cause premature release of neurotransmitter

Neurotransmitter Deactivation
prevents clogging of comm. 2 mechanisms: 1. reuptake more common neurotransmitters drawn back into presynaptic buttons & repackaged in vesicles 2. enzymatic degradation broken apart in synapse by enzymes e.g. acetylcholine broken down by acetylcholinesterase
fig. 4.14

Neurotransmitter Molecules
2 general kinds: small & large (peptides) small: synthesized in cytoplasm of button packaged in synaptic vesicles by Golgi complex peptides: assembled in cytoplasm of cell body on ribosomes packaged in vesicles by cell bodys Golgi complex transported to buttons by microtubules

Neurotransmitter molecules (cont.)

4 classes of small-molecule neurotransmitters 1. amino acids 2. monoamines 3. soluble gases 4. acetylcholine large-molecule neurotransmitters * peptides

Common neurotransmitters
most produce either excitation or inhibition, not both a few produce excitation when binding to some receptor subtypes, and inhibition for other subtypes

Amino Acid Neurotransmitters

vast majority of fast-acting, directed synapses 4 most common: 1. glutamate 2. aspartate 3. glycine 4. gamma-aminobutyric acid (GABA)

> glutamate: most prevalent excitatory neurotransmitter in vertebrate brain and in most excitatory neuromuscular junctions in insects. Aspartate is also an excitatory neurotransmitter > GABA: most common inhibitory neurotransmitter (and glycine also inhibitory)

Monoamine Neurotransmitters
synthesized from a single amino acid (mono) effects more diffuse than amino acid neurotransmitters mostly operate in cells located in brain stem neurons often have highly branched axons with many varicosities monoamines diffusely released

Monoamine Neurotransmitters (cont.)

Contain amine group but lack acid group characterizing amino acids 4 major monoamine neurotransmitters: 1. dopamine 2. norepinephrine 3. epinephrine 4. serotonin

Monoamines (in the order of their synthesis):

from phenylalanine and tyrosine: dopamine (da) norepinephrine (ne/noradrenaline) epinephrine (epi/adrenaline) from tryptophan: serotonin (5ht/5-hydroxytryptamine) from histidine: histamine (?)

 Catacholamines amines containing catacol group (six carbon ring with 2 OH groups) main ones dopamine, epinephrine (adrenaline), norepinephrine (noradrenaline) serotonin and dopamine have influence on a variety of behaviors from mood to movement, neurons using them widespread

 norephinephrine released by sympathetic postganglionic neurons in autonomic NS, also important neurotransmitter in CNS Histamine, octopamine, serotonin, octopamine important in invertebrate nervous systems

Biogenic amines:
acetylcholine (ACh) Other: nitric oxide (NO) carbon monoxide (CO) Anandamide

Acetylcholine
small-molecule neurotransmitter the neurotransmitter at neuromuscular junctions of vertebrate somatic muscles also involved in insect nervous system, also may act presynaptically in vertebrate brain transmit muscle activation signals from brain also in other places in autonomic nervous system and in CNS neurons releasing acetylcholine are called cholinergic neurons

A micellany of substances with no special chemical relationship:

Adenosine triphosphate (ATP) coreleased with catacholamines, may have separate transmitter function, especially in autonomic NS

Many other substances may act as neurotransmitters, with new candidates identified every year

Soluble-Gas Neurotransmitters
recently discovered class of neurotransmitters nitric oxide & carbon monoxide produced in neural cytoplasm, neither stored nor released from vesicles, but synthesized as needed easily pass through membranes, diffuse through cell membrane and then into nearby cells

 effect is neuromodulatory, interact directly with biochemical machinery of target neuron rather than with a specific receptor stimulate production of second messenger then immediately broken down sometimes retrograde transmission from postsynaptic neuron back to presynaptic neuron

Neuropeptides
over 50 peptides qualify as neurotransmitters incl. endorphins endogenous opiates opiate drugs (opium, morphine, heroin) bind to their receptors activate neural systems mediating analgesia (pain suppression) and pleasure

Neuropeptides (cont.)
substance P ?? this should fit in a group opioids: enkephaline dynorphin neurohypophyseals: vasopressin oxytocin secretins: gastric inhibitory peptide ?? hormone-releasing peptide ?? insulins: insulin gastrins: gastrin cholecystokinin somatostatins: pancreatic polypeptides ??

neuropeptides (cont) characteristics:

small chains of amino acids, neurotransmitter role, discovered more recently substance P involved in conveying pain information in vertebrates endorphins important in amelieorating pain most are co-transmitters, substances released along with another neurotransmitter from a synapse, proctolin released along with glutamate at invertebrate neuromuscular junction

Table of Neurotransmitters
Transmitter Molecule Acetylcholine Serotonin 5-Hydroxytryptamine (5-HT) Derived From Choline Tryptophan Site of Synthesis CNS, parasympathetic nerves CNS, chromaffin cells of the gut, enteric cells

GABA
Glutamate Aspartate Glycine Histamine Epinephrine synthesis pathway Norpinephrine synthesis pathway Dopamine synthesis pathway Adenosine ATP Nitric oxide, NO

Glutamate

CNS
CNS CNS spinal cord

Histidine Tyrosine

hypothalamus adrenal medulla, some CNS cells

Tyrosine

CNS, sympathetic nerves

Tyrosine ATP

CNS CNS, periperal nerves sympathetic, sensory and enteric nerves

Arginine

CNS, gastrointestinal tract