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Life cycle of a neurotransmitter Neurotransmitters are chemicals that are synthesised in the presynaptic neurone, which then diffuse across the synaptic cleft and bind to receptors found on the post synaptic membrane. These molecules play a key role in the linking of two cells in a chemical synapse as it enables an action potential generated in a presynaptic membrane to be transmitted to the post synaptic membrane. The prescence of neurotransmitters in chemical synapses was proved by Loewi. The experiment involved an isolated frog heart which had been cannulated in order to release the substances produced by the heart into the external solution. The frog heart was then electrically stimulated through the vagus nerve until the heart rate slowed. After this, the fluid surrounding the heart was collected and added to the heart of a second frog which had no vagus or sympathetic nerves. The addition of the fluid to the second heart also triggered a decrease in heart rate even though there was no electrical stimulation. This proved that a substance, now known as the neurotransmitter, was released by the vagus nerve in first heart as a result of electrical stimulation and it was this molecule which resulted in the heart rate decreasing in both hearts. For a molecule to be classified as a neurotransmitter it must have the three following properties. It should be synthesised in the presynaptic terminal of a neuron and be released in sufficient quantities to trigger an action potential in the post synaptic neuron or an effector. The next criteria is that if the neurotransmitter is applied as a drug it should mimic the same action as it would work if synthesised internally and finally there should be specific mechanisms for removing the neurotransmitter from its site of action. There are two main classes of neurotransmitters; amino acids (glutamate, GABA and glycine) and bioactive amines (acetylcholine, Dopamine, serotonin and noradrenalin). In the following paragraphs the synthesis, storage, release and break down of three neurotransmitters (acetylcholine, catecholamines and GABA) will be considered. Acetylcholine is the common neurotransmitter found in neuromuscular junctions which is responsible for initiating an action potential in skeletal muscles which then trigger contractions. The neurotransmitter acetylcholine is synthesised when choline and acetyl CoA react together and this reaction is catalysed by the enzyme choline acetyl-transferase. The enzyme transfers the acetyl group from acetyl coenzyme A to the choline molecule which is transported into the presynaptic terminal using a choline carrier. The rate limiting step in the synthesis of acetyl choline is the transport of choline and this step can be inhibited which results in the formation of acetylcholine being prevented. The drug hemicholinium blocks the choline transport protein which prevents choline being transported into the presynaptic terminal. Therefore the acetylcholine synthesis is inhibited. After the production of the neurotransmitter it is then packaged into vesicles. When the vesicle reaches the nerve terminal the non peptide neurotransmitter, acetylcholine, moves into the vesicle through the acetylcholine-proton exchanger by secondary active transport. The efflux of protons down the concentration gradient is coupled with the uptake of
acetylcholine. The concentration gradient for the hydrogen ions is maintained by the proton pump which uses the hydrolysis of ATP to actively transport hydrogen ions into the vesicle. Once each synaptic vesicle is filled with 6000 to 10000 molecules of acetyl choline, the vesicles are docked in the active zones of the presynaptic membrane. Once an action potential is stimulated in the presynaptic neurone, voltage gated ion calcium ion channels open which leads to an influx of calcium ions. The increase in calcium ion concentration stimulates the vesicles packed with acetylcholine to fuse with the presynaptic membrane. There are series of stages that are involved with the fusion of synaptic vesicles. Firstly the synaptic vesicles which contain the proteins, synaptotagmin and synaptobrevin within the plasma membrane move towards the axon terminal membrane. The membrane of the axon terminal contains proteins syntaxin and SNAP-25. The next stage is the dissociation of n-Sec-1 which forms a cap over the syntaxin protein. This liberates syntaxin which then winds around SNAP 25 to form a complex. The membrane protein synaptobrevin found in the synaptic vesicle then coils around the syntaxin/SNAP-25 complex and forms a ternary complex. The three proteins continue to wind around each other and form a tight bundle of alpha helices. This action draws the synaptic vesicle towards the presynaptic membrane. In the bacterial infection caused by 'clostridium botulinum' the toxin botulinum is released. This toxin cleaves to the three proteins that form the ternary structure and as a result prevent the fusion of the synaptic vesicles. Due to this the neurotransmitter is not released into the synaptic cleft. However these neurotoxins have a medical use. The botulinum toxin is used to treat muscle spasms and also found in Botox which is a temporary treatment for facial wrinkles. Following the movement of the synaptic vesicles towards the presynaptic membrane, the influx of calcium ions and its binding to synaptotagmin triggers the excocytotic fusion of the vesicle. This releases the neurotransmitter acetylcholine which diffuses across the synaptic cleft. After a few milliseconds of the neurotransmitter being released into the synaptic cleft, it is automatically broken down and the components of the neurotransmitter are reabsorbed into the presynaptic membrane. The enzyme acetylcholinesterase which is present in the synaptic fluid hydrolyses acetylcholine into choline and acetate in a two step process. First the enzyme detaches the choline from the acetylcholine molecule and this forms the intermediate where acetate is covalently coupled to the serine group of the enzyme. The next step is the hydrolysis of the intermediate which releases the acetate molecule. The choline is then reabsorbed into the presynaptic membrane through a secondary active transport mechanism. The uptake of choline is coupled with the diffusion of sodium ions into the presynaptic membrane. Once inside the presynaptic neurone, the choline binds to acetyl coA, which is formed from the oxidation of pyruvate to form acetyl choline. The understanding of these mechanisms has led to the development of anticholinesterase molecules which inhibit the action of the enzyme
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