Mouse islets were used to study whether mobilization of intracellular Ca2+ is sufficient to account for acetylcholine (ACh) amplification of glucose-induced insulin release. In the presence of 15 mM glucose, the acceleration of 45Ca efflux and insulin release by 1–100μM ACh increased with the concentration of extracellular Ca2+ (0.25–2.5 mM). Low concentrations of the Ca2+-channel blockers D 600 (1 μM) or nifedipine (0.1 μM) partially inhibited glucose-induced insulin release and its amplification by ACh. At higher concentrations, D 600 (25 μM) or nifedipine (2 μM) practically abolished the ionic and secretory effects of 1 μM ACh. However, 100 μM ACh still caused a fast, large, but transient acceleration of 45Ca efflux, accompanied by a small, short-lived release of insulin. Similar results were obtained in a Ca2+-free medium, indicating that this peak of 45Ca efflux reflects Ca2+ mobilization. Addition of nifedipine or omission of Ca2+ during ACh stimulation rapidly and strongly inhibited 45Ca efflux and insulin release. Both glucose and ACh induced 45Ca uptake were inhibited by D 600. Only high concentrations of ACh (100 μM) mobilize enough cellular Ca2+ to trigger a small and transient insulin release when Ca2+ influx is prevented or impossible. A continuous influx ofCa2+ is necessary for low ACh concentrations to increase release and for high concentrations to have a sustained effect. The amplification of release by the neurotransmitter results from a slight enhancement of Ca2+ influx associated with a marked increase in the effectiveness of incoming Ca2+ on the releasing machinery.

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