Mechanisms and physiological significance of the cholinergic control of pancreatic β-cell function

Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic nerve endings during the preabsorptive and absorptive phases of feeding. In beta -cells, ACh binds to muscarinic M-3 receptors and exerts complex effects, which culminate in an increase of glucose (nutrient)induced insulin secretion. Activation of PLC generates diacylglycerol. Activation of PLA(2) produces arachidonic acid and lysophosphatidylcholine. These phospholipid-derived messengers, particularly diacylglycerol, activate PKC, thereby increasing the efficiency of free cytosolic Ca2+ concentration ([Ca2+](c)) on exocytosis of insulin granules. IP3, also produced by PLC, causes a rapid elevation of [Ca2+](c) by mobilizing Ca2+ from the endoplasmic reticulum; the resulting fall in Ca2+ in the organelle produces a small capacitative Ca2+ entry. ACh also depolarizes the plasma membrane of beta -cells by a Na+-dependent mechanism. When the plasma membrane is already depolarized by secretagogues such as glucose, this additional depolarization induces a sustained increase in [Ca2+](c). Surprisingly, ACh can also inhibit voltage-dependent Ca2+ channels and stimulate Ca2+ efflux when [Ca2+](c) is elevated. However, under physiological conditions, the net effect of ACh on [Ca2+](c) is always positive. The insulinotropic effect of ACh results from two mechanisms: one involves a rise in [Ca2+](c) and the other involves a marked, PKC-mediated increase in the efficiency of Ca2+ on exocytosis. The paper also discusses the mechanisms explaining the glucose dependence of the effects of ACh on insulin release.