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J Biol Chem, Vol. 274, Issue 41, 29519-29528, October 8, 1999

Depolarization Affects the Binding Properties of Muscarinic Acetylcholine Receptors and Their Interaction with Proteins of the Exocytic Apparatus

Nili Ilouz, Leora Branski, Julia Parnis, Hanna Parnas^§, and Michal Linial^§

From the  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

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 (K_d of ~20 nM) and they shift to a low affinity state (K_d 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.

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