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J Biol Chem, Vol. 274, Issue 41, 29519-29528, October 8, 1999
From the Membrane depolarization is the signal that
triggers release of neurotransmitter from nerve terminals. As a result
of depolarization, voltage-dependent Ca2+
channels open, level of intracellular Ca2+ increases. and
release of neurotransmitter commences. Previous study had shown that in
rat brain synaptosomes, muscarinic acetylcholine (ACh) receptors
(mAChRs) interact with soluble NSF attachment protein receptor proteins
of the exocytic machinery in a voltage-dependent manner. It
was suggested that this interaction might control the rapid,
synchronous release of acetylcholine. The present study investigates
the mechanism for such a voltage-dependent interaction. Here we show that depolarization shifts mAChRs, specifically the m2
receptor subtype, to a low affinity state toward its agonists. At
resting potential, mAChRs are in a high affinity state
(Kd of ~20 nM) and they shift to a
low affinity state (Kd of tens of µM)
upon membrane depolarization. In addition, interaction between m2
receptor subtype and the exocytic machinery increases with receptor
occupancy. Both phenomena are independent of Ca2+ influx.
We propose that these results may explain control of ACh release from
nerve terminals. At resting potential the exocytic machinery is clamped
due to its interaction with the occupied mAChR and depolarization
relieves this interaction. This, together with Ca2+ influx,
enables release of ACh to commence.
Depolarization Affects the Binding Properties of Muscarinic
Acetylcholine Receptors and Their Interaction with Proteins of the
Exocytic Apparatus
,,,§
Department of Biological Chemistry
and the § Otto Loewi Center for Molecular and Cellular
Neurobiology, Alexander Silberman Institute of Life Sciences, The
Hebrew University, Jerusalem 91904, Israel
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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