Anatomy of neurotransmitters
An understanding of the
synaptic transmission is of great importance in understanding the basic
principle of chemical signaling between the neurons. This chemical process of
interaction or signaling between the neurons occurs at the end of the axon, in
a structure called synapse.
Synapse:
As neurons form a
network, so they have to be interconnected for the purpose of transmission of
nerve impulse from one neuron to the other. But, unlike other cells there is a
lack of a cellular continuity between two neurons, as they have a space between
them called as the synapse.
The mechanism of
chemical signaling involves the release of a chemical, called a
neurotransmitter from a presynaptic neuron, which further binds to the
receptors which are located in the postsynaptic neuron. These neurotransmitters
then act on their particular receptors and produce a particular response.
Neurotransmitters:
Neurotransmitters are
defined as endogenous chemicals in the brain which are responsible for the
transmission of the nerve impulse or neuronal signals from one neuron to the
other via a synapse. It has been
mentioned before, that every transmission of the signals requires an optimum
amount of the neurotransmitters in the synaptic cleft. So, neurons have developed
a proper system for keeping a balance in the synthesis, storage, release,
binding, degradation and the recycling of neurotransmitters. Because a failure
to attain this balance can lead to certain metabolic disorders in the body like
disturbance in sleep, mood, weight etc. (1)
There are two
categories of the neurotransmitters:
1.
Small molecule neurotransmitters.
2.
Neuropeptide or peptide transmitters.
Small molecule neurotransmitters
are synthesized at the terminal site of the axon. The enzymes needed for the
synthesis of these neurotransmitters are synthesized within the cell body of
the neuron and are then shifted to the nerve terminal cytoplasm by means of the
process called as slow axonal transport. These enzymes then generate a pool of
neurotransmitters in the cytoplasm.
The mechanism involved
in the synthesis of neuropeptides is different from the small molecule
neuropeptides, however, it is almost similar to the synthesis of the secretory
proteins made by the cells. First of all, gene transcription takes place within
the nucleus of the cell; this process involves the construction of the
corresponding strand of messenger RNA by using a peptide coding sequence of DNA
as a template. The messenger RNA then acts as a code to form a sequence of
amino acids, thus finally forming the neuropepdtide needed at the nerve
terminal. (2)
Some of the important
neurotransmitters with regard to the pschopharmacology are:
Acetylcholine:
Acetylcholine is
basically synthesized by the combination of two compounds;choline and
acetyl-CoA and this reaction is
catalyzed by the enzyme choline acetyletransferase. After the synthesis it is
stored in the vesicles to prevent the degradation by the enzyme
acetylecholinesterase. Acetylcholine is further released as a response of the
action potential moving along the motor neuron and carries the depolarization
wave to the terminal buttons at the presynaptic junction of the neuron. Once
acetylcholine activates its receptor to transmit the signal, there are seens
many downstream effects depending on the fact that which receptor is activated.
The two main receptors
on which acetylcholine acts are muscuranic and nicotinic receptors. Nicotinic
receptors are lignad gated ion channels which when bind to acetylcholine,
undergoes a change that then cause the influx of the NA ions, resulting in the
depolarization of the effector cells. Whereas, muscuranic receptors respond to
both muscurine and acetylcholine. All muscuranic receptors are G protein
coupled receptors and are further classified as M1, M2, M3, M4 and M5.
Norepinephrine:
This neurotransmitter
plays an important in the conditions related to the stress. It enables the body
to flee or fight in emergencies by stimulating the heart rate, blood
circulation and respiration to compensate an increased amount of oxygen for the
muscles. It is the primary neurotransmitter for post ganglionic
sympathetic adrenergic nerves. It is
synthesized within the nerve axon and is further stores in the vesicles and are
released when the action potential travels in a downward direction in a nerve.
The 1st step in the synthesis involves the transport of tyrosine
into the sympathetic nerve axon where tyrosine is converted to the DOPA by the
enzyme tyrosine hydroxylase. DOPA then gets converted to the Dopamine, which is
then on reaching vesicles converted into Noepinephrine by Dopamine beta
hydroxylase enzyme. The norepinephrine thus produced is then released into the
extracellular space by an increased intracellular calcium level. Besides increased
levels of intracellular calcium level, there are various other factor which
trigger the release of norepinephrine like cyclic nucleotides,
phosphodiesterase inhibitors, beta-adrenoceptor agonists, cholinergic nicotinic
agonists, and angiotensin.
Norepinephrine is
metabolized by the enzyme Catechol-o-Methyltransferase. The final product formed
due to this metabolism is termed as Vanillylmandelic acid. (3)
Dopamine:
Dopamine is also
synthesized by the enzyme tyrosine. Tyrosine is converted to the Dopamine with
the help of enzymes called as tyrosine hydroxylase and 1-amino acid
decarboxylase. The neurotransmitters are then stored in the vesicles of the
dopaminergic neurons. Like norepinephrine the exocytosis of the Dopamine also
involve the increased influx of the Calcium ions within
the neuron. This influx causes
the release of the dopamine in the extracellular space.
Reuptake of the
dopamine is caused by two types of transporters named as dopamine transporter
(DAT) and Vesicular monoamine transporter(VMAT). The function of the DAT is to
transport the dopamine from the extracellular space to the intracellular space
and VMAT is responsible for reloading the Dopamine into the vesicles. Dopamine
reuptake inhibitors helps to sustain the levels of the dopamine. The main
enzymes involved in the metabolism of the Dopamine are MAO and COMT. (4)
Serotonin:
The biosynthesis of
serotonin involve the conversion of L-tryptophan to the 5-hydroxytryptophan
with the help of the enzyme L-tryptophan hydroxylase. The final step involves
the process of decarboxylation of 5-hydroxytryptophan by the enzyme L-aromatic
amino acid decarboxylase. Metabolism of the serotonin is carried out by the
enzyme MAO.
The main function of
the serotonin neurotransmitter is to keep a balance in the physiological
processes like sensory perception, mood and depression. As the presence id
serotonin is very important for the maintenance of these metabolic functions,
so Selective serotonin reuptake inhibitors help in this regard by decreasing
the rate at which this neurotransmitter is reabsorbed, thus causing an increase
in the serotonin levels in the synaptic cleft.(5)
GABA:
The neurotransmitter
GABA synthesized from Glutamate with the help of enzyme Glutamate decarboxylase
in the GABAergic neurons. The neurotransmitters are then transported into the
vesicles with the help of vesicular transporters. Upon release these
neurotransmitters are taken up with the help of the membrane transporters into
the neurons where they can be recycled and metabolized with the help of their
respective enzymes.(6)
References:
2. Purves D, Augustine GJ, Fitzpatrick D, et al, (2001).
'Neurotransmitter synthesis'. In: NeuroscieSunderland (MA): Sinauer
Associatesnce (ed), neurosience. 2nd ed.
3.
Weiner N. (e.g. 2011). Multiple
factors regulating the release of norepinephrine consequent to nerve
stimulation.. [ONLINE] Available at: 3.
http://www.ncbi.nlm.nih.gov/pubmed/36304
http://www.ncbi.nlm.nih.gov/pubmed/36304
6.
Fabian C. Roth and Andreas Draguhn,
(2012). '6. GABA Metabolism and Transport: Effects on Synaptic Efficacy'. In:
e.g. Tolkien, J.R.R. (ed), Neural Plasticity. 1st ed. : . pp.12.
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