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

  • Gilon P
  • Henquin J
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Abstract

Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic nerve endings during the preabsorptive and absorptive phases of feeding. In β-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 β-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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Gilon, P., & Henquin, J.-C. (2001). Mechanisms and Physiological Significance of the Cholinergic Control of Pancreatic β-Cell Function. Endocrine Reviews, 22(5), 565–604. https://doi.org/10.1210/edrv.22.5.0440

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