Diversity and Functions
By Michael W. King, Ph.D
The Following for More Details
Table of Neurotransmitters
Many other neurotransmitters are derived from
precursor proteins, the so-called peptide neurotransmitters.
As many as 50 different peptides have been shown to exert their effects
on neural cell function. Several of these peptide transmitters are derived
from the larger protein pre-opiomelanocortin
(POMC). Neuropeptides are responsible for mediating sensory and emotional
responses including hunger, thirst, sex drive, pleasure and pain.
Synaptic transmission refers to the propagation
of nerve impulses from one nerve cell to another. This occurs at a specialized
cellular structure known as the synapse---
a junction at which the axon of the presynaptic neuron terminates at some
location upon the postsynaptic neuron. The end of a presynaptic axon, where
it is juxtaposed to the postsynaptic neuron, is enlarged and forms a structure
known as the terminal button. An axon
can make contact anywhere along the second neuron: on the dendrites (an
synapse), the cell body (an axosomatic
synapse) or the axons (an axo-axonal
Nerve impulses are transmitted at synapses
by the release of chemicals called neurotransmitters.
As a nerve impulse, or action potential,
reaches the end of a presynaptic axon, molecules of neurotransmitter are
released into the synaptic space. The neurotransmitters are a diverse group
of chemical compounds ranging from simple amines such as dopamine
and amino acids such as g-aminobutyrate (GABA),
to polypeptides such as the
The mechanisms by which they elicit responses in both presynaptic and postsynaptic
neurons are as diverse as the mechanisms employed by growth factor and
A different type of nerve transmission occurs
when an axon terminates on a skeletal muscle fiber, at a specialized structure
called the neuromuscular junction.
An action potential occurring at this site is known as neuromuscular
transmission. At a neuromuscular junction, the axon subdivides
into numerous terminal buttons that reside within depressions formed in
the motor end-plate. The particular
transmitter in use at the neuromuscular junction is acetylcholine.
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Once the molecules of neurotransmitter are
released from a cell as the result of the firing of an action potential,
they bind to specific receptors on the surface of the postsynaptic cell.
In all cases in which these receptors have been cloned and characterized
in detail, it has been shown that there are numerous subtypes of receptor
for any given neurotransmitter. As well as being present on the surfaces
of postsynaptic neurons, neurotransmitter receptors are found on presynaptic
neurons. In general, presynaptic neuron receptors act to inhibit further
release of neurotransmitter.
The vast majority of neurotransmitter receptors
belong to a class of proteins known as the serpentine
receptors. This class exhibits a characteristic transmembrane
structure: that is, it spans the cell membrane, not once but seven times.
The link between neurotransmitters and intracellular signaling is carried
out by association either with G-proteins (small GTP-binding and hydrolyzing
proteins) or with protein kinases, or by the receptor itself in the form
of a ligand-gated ion channel (for example, the acetylcholine receptor).
One additional characteristic of neurotransmitter receptors is that they
are subject to ligand-induced desensitization:
That is, they can become unresponsive upon prolonged exposure to their
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is a simple molecule synthesized from choline and acetyl-CoA through the
action of choline acetyltransferase. Neurons that synthesize
and release ACh are termed cholinergic neurons.
When an action potential reaches the terminal button of a presynaptic neuron
a voltage-gated calcium channel is opened. The influx of calcium ions,
Ca2+, stimulates the exocytosis of presynaptic vesicles containing
ACh, which is thereby released into the synaptic cleft. Once released,
ACh must be removed rapidly in order to allow repolarization to take place;
this step, hydrolysis, is carried out by the enzyme, acetylcholinesterase.
The acetylcholinesterase found at nerve endings is anchored to the plasma
membrane through a glycolipid.
ACh receptors are ligand-gated cation channels
composed of four different polypeptide subunits arranged in the form [(a2)(b)(g)(d)].
Two main classes of ACh receptors have been identified on the basis of
their responsiveness to the toadstool alkaloid, muscarine, and to nicotine,
respectively: the muscarinic receptors
and the nicotinic receptors. Both receptor
classes are abundant in the human brain. Nicotinic receptors are further
divided into those found at neuromuscular junctions and those found at
neuronal synapses. The activation of ACh receptors by the binding of ACh
leads to an influx of Na+ into the celland an efflux of K+,
resulting in a depolarization of the postsynaptic neuron and the initiation
of a new action potential.
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Cholinergic Agonists and
Numerous compounds have been identified that
act as either agonists or antagonists of cholinergic neurons. The principal
action of cholinergic agonists is the excitation or inhibition of autonomic
effector cells that are innervated by postganglionic parasympathetic neurons
and as such are refered to as parasympathomimetic
agents. The cholinergic agonists include choline esters (such
as ACh itself) as well as protein- or alkaloid-based compounds. Several
naturally occurring compounds have been shown to affect cholinergic nerons,
either positively or negatively.
The responses of cholinergic neurons can also
be enhanced by administration of cholinesterase (ChE) inhibitors. ChE inhibitors
have been used as components of nerve gases but also have significant medical
application in the treatment of disorders such as glaucoma and myasthenia
gravis as well as in terminating the effects of neuromuscular blocking
agents such as atropine.
Natural Cholinergic Agonist and
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||Alkaloid prevalent in the tobacco
||Activates nicotinic class of
ACh receptors, locks the channel open
||Alkaloid produced by Amanita
||Activates muscarinic class
of ACh receptors
||Protein produced by the black
||Induces massive ACh release,
possibly by acting as a Ca2+ ionophore
|Atropine (and related compound
||Alkaloid produced by the deadly
||Blocks ACh actions only at
||Eight proteins produced by
||Inhibits the release of ACh
||Protein produced by Bungarus
genus of snakes
||Prevents ACh receptor channel
||Active ingredient of curare
||Prevents ACh receptor channel
opening at motor end-plate
The principal catecholamines are norepinephrine,
and dopamine. These compounds are formed
from phenylalanine and tyrosine. Tyrosine is produced in the liver from
phenylalanine through the action of phenylalanine hydroxylase.
The tyrosine is then transported to catecholamine-secreting neurons where
a series of reactions convert it to dopamine, to norepinephrine and finally
to epinephrine (see Specialized
Products of Amino Acids).
Catecholamines exhibit peripheral nervous
system excitatory and inhibitory effects as well as actions in the CNS
such as respiratory stimulation and an increase in psychomotor activity.
The excitatory effects are exerted upon smooth muscle cells of the vessels
that supply blood to the skin and mucous membranes. Cardiac function is
also subject to excitatory effects, which lead to an increase in heart
rate and in the force of contraction. Inhibitory effects, by contrast,
are exerted upon smooth muscle cells in the wall of the gut, the bronchial
tree of the lungs, and the vessels that supply blood to skeletal muscle.
In addition to their effects as neurotransmitters,
norepinephrine and epinephrine can influence the rate of metabolism. This
influence works both by modulating endocrine function such as insulin secretion
and by increasing the rate of glycogenolysis and fatty acid mobilization.
The catecholamines bind to two different classes
of receptors termed the a- and b-adrenergic receptors. The catecholamines
therefore are also known as adrenergic neurotransmitters;
neurons that secrete them are adrenergic neurons.
Norepinephrine-secreting neurons are noradrenergic.
The adrenergic receptors are classical serpentine receptors that couple
to intracellular G-proteins. Some of the norepinephrine released from presynaptic
noradrenergic neurons recycled in the presynaptic neuron by a reuptake
Epinephrine and norepinephrine are catabolized
to inactive compounds through the sequential actions of catecholamine-O-methyltransferase
(COMT) and monoamine oxidase (MAO). Compounds that inhibit
the action of MAO have been shown to have beneficial effects in the treatment
of clinical depression, even when tricyclic antidepressants are ineffective.
The utility of MAO inhibitors was discovered serendipitously when patients
treated for tuberculosis with isoniazid showed signs of an improvement
in mood; isoniazid was subsequently found to work by inhibiting MAO.
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Serotonin (5-hydroxytryptamine, 5HT)
is formed by the hydroxylation and decarboxylation of tryptophan (see Specialized
Products of Amino Acids). The greatest concentration of 5HT (90%) is
found in the enterochromaffin cells of the gastrointestinal tract. Most
of the remainder of the body's 5HT is found in platelets and the CNS. The
effects of 5HT are felt most prominently in the cardiovascular system,
with additional effects in the respiratory system and the intestines. Vasoconstriction
is a classic response to the administration of 5HT.
Neurons that secrete 5HT are termed serotonergic.
Following the release of 5HT, a portion is taken back up by the presynaptic
serotonergic neuron in a manner similar to that of the reuptake of norepinephrine.
The function of serotonin is exerted upon
its interaction with specific receptors. Several serotonin receptors have
been cloned and are identified as 5HT1, 5HT2, 5HT3,
5HT4, 5HT5, 5HT6, and 5HT7.
Within the 5HT1 group there are subtypes 5HT1A, 5HT1B,
5HT1D, 5HT1E, and 5HT1F. There are three
5HT2 subtypes, 5HT2A, 5HT2B, and 5HT2C
as well as two 5HT5 subtypes, 5HT5a and 5HT5B.
Most of these receptors are coupled to G-proteins that affect the activities
of either adenylate cyclase or phospholipase Cg.
The 5HT3 class of receptors are ion channels.
Some serotonin receptors are presynaptic and
others postsynaptic. The 5HT2A receptors mediate platelet aggregation
and smooth muscle contraction. The 5HT2C receptors are suspected
in control of food intake as mice lacking this gene become obese fromincreased
food intake and are also subject to fatal seizures. The 5HT3
receptors are present in the gastrointestinal tract and are related to
vomiting. Also present in the gastrointestinal tract are 5HT4
receptors where they function in secretion and peristalsis. The 5HT6
and 5HT7 receptors are distributed throughout the limbic system
of the brain and the 5HT6 receptors have high affinity for antidepressant
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Several amino acids have distinct excitatory
or inhibitory effects upon the nervous system. The amino acid derivative,
g-aminobutyrate, also called 4-aminobutyrate, (GABA)
is a well-known inhibitor of presynaptic transmission in the CNS, and also
in the retina. The formation of GABA occurs by the decarboxylation of glutamate
catalyzed by glutamate decarboxylase (GAD).
GAD is present in many nerve endings of the brain as well as in the b-cells
of the pancreas. Neurons that secrete GABA are termed GABAergic.
GABA exerts its effects by binding to two
distinct receptors, GABA-A and GABA-B. The GABA-A receptors form a Cl-
channel. The binding of GABA to GABA-A receptors increases the Cl-
conductance of presynaptic neurons. The anxiolytic drugs of the benzodiazepine
family exert their soothing effects by potentiating the responses of GABA-A
receptors to GABA binding. The GABA-B receptors are coupled to an intracellular
G-protein and act by increasing conductance of an associated K+
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W. King, Ph.D / Medical Biochemistry / Terre Haute Center for Medical Education
Associate Professor of Biochemistry and
Molecular Biology, IU School of Medicine, Associate Professor of Life Sciences,
Indiana State University, Research Professor of Applied Biology and Biomedical
Engineering, Rose-Hulman Institute of Technology, Ph.D., University of
California at Riverside, 1984
Copyright 2000 Universidade Estadual