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Depolarization Initiates Phasic Acetylcholine Release by Relief of a Tonic Block Imposed by Presynaptic M₂ Muscarinic Receptors

¹The Otto Loewi Minerva Center for Cellular and Molecular Neurobiology, Department of Neurobiology, Hebrew University of Jerusalem, Jerusalem; ²Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel; and ³Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive Kidney Diseases, Bethesda, Maryland

Submitted 3 November 2004; accepted in final form 3 February 2005

The role of presynaptic muscarinic autoreceptors in the initiation of phasic acetylcholine (ACh) release at frog and mouse neuromuscular junctions was studied by measuring the dependency of the amount (m) of ACh release on the level of presynaptic depolarization. Addition of methoctramine (a blocker of M₂ muscarinic receptors), or of acetylcholinesterase (AChE), increased release in a voltage-dependent manner; enhancement of release declined as the depolarizing pulse amplitude increased. In frogs and wild-type mice the slope of log m/log pulse amplitude (PA) was reduced from about 7 in the control to about 4 in the presence of methoctramine or AChE. In M₂ muscarinic receptor knockout mice, the slope of log m/log PA was much smaller (about 4) and was not further reduced by addition of either methoctramine or AChE. The effect of a brief (0.1 ms), but strong (–1.2 µA) depolarizing prepulse on the dependency of m on PA was also studied. The depolarizing prepulse had effects similar to those of methoctramine and AChE. In particular, it enhanced release of test pulses in a voltage-dependent manner and reduced the slope of log m/log PA from about 7 to about 4. Methoctramine + AChE occluded the prepulse effects. In knockout mice, the depolarizing prepulse had no effects. The cumulative results suggest that initiation of phasic ACh release is achieved by depolarization-mediated relief of a tonic block imposed by presynaptic M₂ muscarinic receptors.

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