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Endocrine Reviews 22 (5): 565-604
Copyright © 2001 by The Endocrine Society

Mechanisms and Physiological Significance of the Cholinergic Control of Pancreatic ß-Cell Function

Patrick Gilon and Jean-Claude Henquin

Unité d’Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, B-1200 Brussels, Belgium

Correspondence: Address all correspondence and requests for reprints to: Dr. Patrick Gilon, Unité d’Endocrinolgie et Métabolisme, UCL 55.30, Avenue Hippocrate 55, B-1200 Brussels, Belgium. E-mail: gilon{at}endo.ucl.ac.be

Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic nerve endings during the preabsorptive and absorptive phases of feeding. In ß-cells, ACh binds to muscarinic M3 receptors and exerts complex effects, which culminate in an increase of glucose (nutrient)-induced insulin secretion. Activation of PLC generates diacylglycerol. Activation of PLA2 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 ß-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.




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