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ANATOMY OF NEUROTRANSMITTERS



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:
1.      http://www.ncbi.nlm.nih.gov/books/NBK11110/
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
4.      www.wikipedia.com
5.      http://www.pharmacorama.com/en/Sections/Serotonin_2_1.php
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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