Theory for the feedback inhibition of fast release of neurotransmitter.
Autoinhibition of neurotransmitter release occurs via binding of transmitter to appropriate receptors. Experiments have provided evidence suggesting that the control of neurotransmitter release in fast systems is mediated by these inhibitory autoreceptors. Earlier, the authors formulated and analysed a mathematical model for a theory of release control in which these autoreceptors played a key role. The key experimental findings on which the release-control theory is based are: (i) the inhibitory autoreceptor has high affinity for transmitter under rest potential and shifts to low affinity upon depolarization; (ii) the bound (with transmitter) autoreceptor associates with exocytotic machinery Ex and thereby blocks it, preventing release of neurotransmitter. Release commences when depolarization shifts the autoreceptor to a low-affinity state and thereby frees Ex from its association with the autoreceptors. Here we extend the model that describes control of release so that it also accounts for release autoinhibition. We propose that inhibition is achieved because addition of transmitter, above its rest level, causes transition of the complex of autoreceptor and Ex to a state of stronger association. Relief of Ex from this state requires higher depolarization than from the weakly associated complex. In contrast to the weakly associated complex that only requires binding of transmitter to the autoreceptor to be formed, the transition to the strongly associated complex is induced by a second messenger, which is produced as a result of the receptor binding to transmitter. The theory explains the following experimental results (among others): for inhibition via transmitter or its agonists, the magnitude of inhibition decreases with depolarization; a plot of inhibition as a function of the concentration of muscarine (an acetylcholine agonist) yields an S-shaped curve that shifts to the right for higher depolarizations; the time course of release does not change when transmitter is added; the time course of release also does not change when transmitter antagonists are added, although quantal content increases; however, addition of acetylcholine esterase (an enzyme that hydrolyses acetylcholine) prolongs release.
Yusim
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Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel. yusim@wisdom.weizmann.ac.il
Parnas
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Segel
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D000109:Acetylcholine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D000110:Acetylcholinesterase / Q000502:physiology; D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D001665:Binding Sites; D003198:Computer Simulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005246:Feedback / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials; D008954:Models, Biological; D009116:Muscarine / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology*
D017660:Autoreceptors; D018690:Excitatory Amino Acid Agonists; D018727:Muscarinic Antagonists; D018377:Neurotransmitter Agents; D018698:Glutamic Acid; D016202:N-Methylaspartate; D009116:Muscarine; D000110:Acetylcholinesterase; D000109:Acetylcholine