Requirement for the L-type Ca2+ channel α1D subunit in postnatal pancreatic β cell generation

作者：Yoon Namkung, Nataliya Skrypnyk, Myung-jin Jeong, Taehoon Lee, Myung‐Shik Lee, Hyung‐Lae Kim, Hemin R. Chin, Pann‐Ghill Suh, Sung-Sook Kim, Hee‐Sup Shin · 发表于：Journal of Clinical Investigation · 年份：2001 · DOI：10.1172/jci13310 · 被引用次数：125 · 研究领域：Pancreatic function and diabetes、Genetics and Neurodevelopmental Disorders、Diabetes Management and Research

IntroductionVoltage-dependent Ca 2+ channels (VDCCs) provide a pathway for the entry of extracellular Ca 2+ into the cytoplasm in a membrane voltage-dependent manner (1).VDCC is a heteromeric protein complex, composed of a pore-forming α 1 subunit and regularly associated β and disulfide-linked α 2 δ subunits (2).The L-type Ca 2+ channel is defined by its pharmacological sensitivity to dihydropyridines, activation by relatively strong depolarization, and slow inactivation (3).Genes encoding the L-type channels are α 1S , α 1C , α 1D , and α 1F (Ca v 1.1-1.4)(4).Besides excitation-contraction coupling in muscle cells (5), L-type channels play critical roles in hormone or neurotransmitter release (6, 7), synaptic plasticity (8), and regulation of gene expression (9) especially in the nervous and neuroendocrine systems.Two different genes, α 1C and α 1D , encode neuronal L-type channels.The α 1D gene is expressed in various organs including brain, pancreas, heart, and cochlea (10-13).Pancreatic β cells express the two isotypes of the L-type channel, α 1C and α 1D (11, 14).In the β cell, glucose metabolism causes an increase in ATP or the ATP/ADP ratio, which in turn closes K ATP channels.This leads to membrane depolarization, opening of VDCC, influx of Ca 2+ , and a rise in cytosolic free Ca 2+ concentration ([Ca 2+ ] i ).The elevation of [Ca 2+ ] i directly triggers insulin exocytosis.L-type channels are known to play a physiological role in insulin secretion because L-type cha...