Key result
Muscarine inhibits acetylcholine release via two distinct Ca2+-independent mechanisms, with the functional affinity (Ki) of the M2 receptor shifting from 0.23 μM at low depolarization to 8.0 μM at high depolarization.
Feedback inhibition of acetylcholine release by muscarine involves two distinct Ca2+-independent processes: a slow, PTX-sensitive, voltage-dependent mechanism and a fast, PTX-insensitive, voltage-independent mechanism.
The effect of membrane potential on feedback inhibition of acetylcholine (ACh) release was studied using the frog neuromuscular junction. It was found that membrane potential affects the functional affinity (K(i)) of the presynaptic M2 muscarinic receptor. The K(i) for muscarine shifts from approximately 0.23 microm (at resting potential) to approximately 8 microm (at a high depolarization). Measurements of Ca2+ currents in axon terminals showed that the depolarization-mediated shift in K(i) does not stem from depolarization-dependent changes in Ca2+ influx. Pretreatments with pertussis toxin (PTX) abolished the depolarization-dependent shift in K(i); at all depolarizations K(i) was the same and higher (approximately 32 microm) than before PTX treatment. The inhibitory effect of muscarine on ACh release is produced by two independent mechanisms: a slow, PTX-sensitive process, which prevails at low to medium depolarizations and operates already at low muscarine concentrations, and a fast, PTX-insensitive and voltage-independent process, which requires higher muscarine concentrations. Neither of the two processes involves a reduction in Ca2+ influx.
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Slutsky et al. (2002) studied this question. Muscarine vs. Control (no muscarine) was evaluated on Inhibition of acetylcholine release and functional affinity (Ki) of presynaptic M2 muscarinic receptor. Muscarine inhibits acetylcholine release via two distinct Ca2+-independent mechanisms, with the functional affinity (Ki) of the M2 receptor shifting from 0.23 μM at low depolarization to 8.0 μM at high depolarization.
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