Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Caulfield, M. P. (1993). Muscarinic receptors—characterization, coupling and function. Pharmacol. Ther. 58, 319–379.
Dolezal, V. and S. Tucek (1993). Presynaptic muscarinic receptors and the release of acetylcholine from cerebrocortical prisms: role of Ca2+ and K + concentrations. Naunyn Schmiedebergs Arch. Pharmacol. 348, 228–233.
Hamilton, B. R. and D. O. Smith (1991). Autoreceptor-mediated purinergic and cholinergic inhibition of motor nerve terminal calcium currents in the rat. J. Physiol. (Lond.) 432, 327–341.
Ilouz, N., L. Brabski, H. Parnas and M. Linial (1999). Depolarization affects the binding properties of mAChRs and their interaction with proteins of the exocytic apparatus. J. Biol. Chem. 274, 29519–29528.
Khanin, R., H. Parnas and L. A. Segel (1997). First step negative feedback accounts for inhibition of fast neurotransmitter release. J. Theor. Biol. 188, 261–276.
Kloog, Y., R. Galron and M. Sokolovsky (1986). Bisquaternary pyridinium oxides as presynaptic agonists and postsynaptic antagonists of muscarinic receptors. J. Neurochem. 46, 767–772.
Korn, H., C. Sur, S. Charpier, P. Legendre and D. S. Faber (1994). The one-vesicle hypothesis and multivesicular release, in Molecular and Cellular Mechanisms of Neurotransmitter Release, L. Stjärne et al. (Ed.), New York: Raven Press, Chap. 19, pp. 301–322
Land, B. R., E. E. Salpeter and M. M. Salpeter (1980). Acetylcholine receptor site density affects the rising phase of miniature endplate currents. Proc. Natl Acad. Sci. USA 77, 3736–3740.
Lustig, C., H. Parnas and L. A. Segel (1990). Release kinetics as a tool to describe drug effects on neurotransmitter release. J. Theor. Biol. 144, 225–248.
Michaelson, D. M., S. Avissar, Y. Kloog and M. Sokolovsky (1979). Mechanism of acetyl-choline release: possible involvement of presynaptic muscarinic receptors in regulation of acetylcholine release and protein phosporylation. Proc. Natl Acad. Sci. USA 76, 6336–6340.
Mori, M., T. Kamiya, H. Tsushima and T. Matsuda (1993). Regulation of spontaneous acetylcholine release in the hypothalamic vasopressinergic supraoptic nucleus of a freely moving rat: a study by in vivo microdialysis. Jpn. J. Pharmacol. 61, 203–208.
Okano, K., J. R. Monck and J. M. Fernandez (1993). GTPγS stimulates exocytosis in patch-clamped rat melanotrops. Neuron 11, 165–172.
Parnas, I., J. Dudel, H. Parnas and R. Ravin (1996). Glutamate depresses release by activating nonconventional glutamate receptors at crayfish nerve terminals. Eur. J. Neurosci. 8, 116–126.
Parnas, H., M. Flashner and M. E. Spira (1989). Sequential model to describe the nicotinic synaptic current. Biophys. J. 55, 875–884.
Parnas, H., M. Linial and I. Parnas (1997). The role of autoreceptors in initiation of release. Curr. Top. Pharmacol. 3, 177–191.
Parnas, H., I. Parnas, R. Ravin and B. Yudelevitch (1994). Glutamate and NMDA affect release from crayfish axon terminals in a voltage dependent manner. Proc. Natl Acad. Sci. USA 91, 11586–11590.
Parnas, H., L. Segel, J. Dudel and I. Parnas (2000). Autoreceptors, membrane potential and the regulation of transmitter release. Trends Neurosci. 23, 60–68.
Roche, J. P. and S. N. Treistman (1998). The Ca2+ channel β 3 subunit differentially modulates G-protein sensitivity of α 1A and β 1B channels. J. Neurosci. 18, 878–886.
Schoepp, D. D. and P. J. Conn (1993). Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol. Sci. 14, 13–20.
Segel, L. A. and A. Perelson (1991). Exploiting the diversity of time scales in the immune system: a B cell antibody model. J. Stat. Phys. 63, 1113–1131.
Slutsky, I., R. Ravin, I. Silman, I. Parnas and H. Parnas (2000). The time course of release in the frog neuromuscular junction is determined by ACh concentration in the synaptic cleft. Submitted for publication.
Slutsky, I., H. Parnas and I. Parnas (2000). Presynaptic effects of muscarine on ACh release at the frog neuromuscular junction. J. Physiol. (Lond.) 514, 769–782.
Vitale, N., H. Mikai, B. Rouot, D. Thierse, D. Aunis and M. F. Bader (1993). Exocytosis in chromaffin cells. Possible involvement of the heterotrimeric GTP-binding protein. J. Biol. Chem. 268, 14715–14723.
Yusim, K., H. Parnas and L. Segel (1999). Theory of fast neurotransmitter release control based on voltage-dependent interaction between autoreceptors and proteins of the exocytotic machinery. Bull. Math. Biol. 61, 701–725.
Zamponi, G. W. and T. P. Snutch (1998). Decay of prepulse facilitation of N type calcium channels during G protein inhibition is consistent with binding of a single G βγ subunit. Proc. Natl Acad. Sci. USA 95, 4035–4039.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yusim, K., Parnas, H. & Segel, L.A. Theory for the feedback inhibition of fast release of neurotransmitter. Bull. Math. Biol. 62, 717–757 (2000). https://doi.org/10.1006/bulm.2000.0174
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1006/bulm.2000.0174