Chemical structure of 'D-aspartic acid', a common amino acid neurotransmitter.
'Neurotransmitters' are
chemicals that are used to relay, amplify and modulate signals between a
neuron and another
cell. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:
★ It is
synthesized endogenously, that is, within the
presynaptic neuron;
★ It is available in sufficient quantity in the presynaptic neuron to exert an effect on the
postsynaptic neuron;
★ Externally administered, it must mimic the endogenously-released substance; and
★ A
biochemical mechanism for inactivation must be present.
However, there are other materials, such as the
zinc ion, that are neither synthesized nor catabolized (i.e., ''degraded''; see
Anabolism) and are considered neurotransmitters by some. Thus, the old definitions are being revised.
Types of neurotransmitters
There are many different ways to classify neurotransmitters. Often, dividing them into
amino acids,
peptides, and
monoamines is sufficient for many purposes.
Some more precise divisions are as follows:
★ Around 10 "small-molecule neurotransmitters" are known:
★
★
acetylcholine
★
★
monoamines (
norepinephrine NE,
dopamine DA &
serotonin 5-HT)
★
★ 3 or 4 amino acids, depending on exact definition used: (primarily
glutamic acid,
GABA,
aspartic acid &
glycine)
★
★
Purines, (Adenosine,
ATP,
GTP and their derivatives)
★
★ Fatty acids are also receiving attention as the potential
endogenous cannabinoid.
★ Over 50 neuroactive peptides (
vasopressin,
somatostatin,
neurotensin, etc.) have been found, among them hormones such as LH or
insulin that have specific local actions in addition to their long-range signalling properties.
★ Single ions, such as synaptically-released
zinc, are also considered neurotransmitters by some.
The major "workhorse" neurotransmitters of the brain are glutamic acid (=glutamate) and GABA.
Effects
Some examples of neurotransmitter action:
★
Acetylcholine - voluntary movement of the muscles
★
Norepinephrine - wakefulness or arousal
★
Dopamine - voluntary movement and motivation, "wanting"
★
Serotonin - memory, emotions, wakefulness, sleep and temperature regulation
★
GABA (gamma aminobutyric acid) - inhibition of motor neurons
★
Glycine - spinal reflexes and motor behaviour
★
Neuromodulators - sensory transmission-especially pain
It is important to appreciate that it is the receptor that dictates the neurotransmitter's effect.
Mechanism of action
Within the cells, small-molecule neurotransmitters are usually packaged in
vesicles. When an
action potential reaches the cell body, the rapid depolarization causes
calcium ion (Ca2) channels to open. Calcium then stimulates the transport of vesicles to the synaptic membrane and their release at synaptic
boutons - a form of
exocytosis. These neurotransmitters are released in quanta, whereby a single quantum consists of a vesicle containing possibly thousands of neurotransmitters
[1].
The neurotransmitters then
diffuse across the
synaptic cleft to bind to densely and geometrically arranged
receptors. The receptors are broadly classified into
ionotropic and
metabotropic receptors. Ionotropic receptors are ligand-gated ion channels that open or close through neurotransmitter binding. Metabotropic receptors, which can have a diverse range of effects on a cell, transduct the signal by secondary messenger systems, or
G-proteins.
Neuroactive
peptides are made in the neuron's
soma and are transported through the
axon to the synapse. They are usually packaged into dense-core vesicles and are released through a similar, but metabolically distinct, form of exocytosis used for small-molecule synaptic vesicles.
Post-synaptic effect
A neurotransmitter's effect is determined by its receptor. For example,
GABA can act on both rapid or slow inhibitory receptors (the
GABA-A and
GABA-B receptor respectively). Many other neurotransmitters, however, may have
excitatory or
inhibitory actions depending on which receptor they bind to.
Neurotransmitters may cause either excitatory or inhibitory post-synaptic potentials. That is, they may help the initiation of a nerve impulse in the receiving neuron, or they may discourage such an impulse by modifying the local membrane voltage potential. In the central nervous system, combined input from several synapses is usually required to trigger an action potential.
Glutamate is the most prominent of excitatory transmitters;
GABA and
glycine are well-known inhibitory neurotransmitters.
Many neurotransmitters are removed from the synaptic cleft by
neurotransmitter transporters in a process called ''
reuptake'' (or often simply 'uptake'). Without reuptake, the molecules might continue to stimulate or inhibit the firing of the postsynaptic neuron. Another mechanism for removal of a neurotransmitter is digestion by an
enzyme. For example, at cholinergic synapses (where
acetylcholine is the neurotransmitter), the enzyme
acetylcholinesterase breaks down the acetylcholine. Neuroactive peptides are often removed from the cleft by diffusion, and eventually broken down by proteases.
Specifications
While some neurotransmitters (glutamate, GABA, glycine) are used very generally throughout the central nervous system, others can have more specific effects, such as on the
autonomic nervous system, by both pathways in the
sympathetic nervous system and the
parasympathetic nervous system, and the action of others are regulated by distinct classes of nerve clusters which can be arranged in familiar pathways around the brain. For example,
Serotonin is released specifically by cells in the brainstem, in an area called the
raphe nuclei, but travels around the brain along the
medial forebrain bundle activating the
cortex,
hippocampus,
thalamus,
hypothalamus and
cerebellum. Also, it is released in the Caudal serotonin nuclei, so as to have effect on the spinal cord. In the peripherial nervous system (such as in the gut wall) serotonin regulates vascular tone.
Dopamine classically modulates two systems: the brain's reward mechanism, and movement control.
Neurotransmitters that have these types of specific actions are often targeted by drugs.
★
Cocaine, for example, blocks the reuptake of
dopamine, leaving these neurotransmitters in the
synaptic gap longer.
★
Prozac is a
selective serotonin reuptake inhibitor (SSRI), hence potentiating the effect of naturally released serotonin.
★
AMPT prevents the conversion of tyrosine to
L-DOPA, the precursor to dopamine;
reserpine prevents dopamine storage within
vesicles; and
deprenyl inhibits
monoamine oxidase (MAO)-B and thus increases dopamine levels.
Some neurotransmitter/neuromodulators like zinc not only can modulate the sensitivity of a
receptor to other neurotransmitters (
allosteric modulation) but can even penetrate specific, gated channels in post-synaptic neurons, thus entering the post-synaptic cells. This "translocation" is another mechanism by which synaptic transmitters can affect postsynaptic cells.
Diseases may affect specific neurotransmitter pathways. For example,
Parkinson's disease is at least in part related to failure of dopaminergic cells in
deep-brain nuclei, for example the
substantia nigra. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
Common neurotransmitters
See also
★
Neuropsychopharmacology
★
Nervous system
External links
★
Molecular Expressions Photo Gallery: The Neurotransmitter Collection
★
Brain Neurotransmitters
★
Endogenous Neuroactive Extracellular Signal Transducers
★
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