The processes involved in neurochemical transmission in a cholinergic neuron are shown in Figure 9.2. The initial substrates for the synthesis of acetylcholine are glucose and choline. Glucose enters the neuron by means of facilitated transport. There is some disagreement as to whether choline enters cells by active or facilitated transport. Pyruvate derived from glucose is transported into mitochondria and converted to acetylcoenzyme A (acetyl-CoA). The acetyl-CoA is transported back into the cytosol. With the aid of the enzyme choline acetyl-transferase, acetylcholine is synthesized from acetyl-CoA and choline. The acetylcholine is then transported into and stored within the storage vesicles by as yet unknown mechanisms.
Conduction of an action potential through the terminal branches of an axon causes depolarization of the varicosity membrane, resulting in the release of transmitter molecules via exocytosis. Once in the junctional extracellular space (biophase), acetylcholine interacts with cholinoreceptors.
A key factor in the process of exocytosis is the entry of extracellular calcium ions during the depolarization.
Modification of extracellular calcium concentration or of calcium entry therefore can markedly affect neurotransmission.
The interactions between transmitters and their receptors are readily reversible, and the number of transmitter-receptor complexes formed is a direct function of the amount of transmitter in the biophase. The length of time that intact molecules of acetylcholine remain in the biophase is short because acetylcholinesterase, an enzyme that rapidly hydrolyzes acetylcholine, is highly concentrated on the outer surfaces of both the prejunc-tional (neuronal) and postjunctional (effector cell) membranes. A rapid hydrolysis of acetylcholine by the enzyme results in a lowering of the concentration of free transmitter and a rapid dissociation of the transmitter from its receptors; little or no acetylcholine escapes into the circulation. Any acetylcholine that does reach the circulation is immediately inactivated by plasma esterases.
The rapid removal of transmitter is essential to the exquisite control of neurotransmission. As a consequence of rapid removal, the magnitude and duration of effect produced by acetylcholine are directly related to the frequency of transmitter release, that is, to the frequency of action potentials generated in the neuron.
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