Electrophysiology of islet cells 10

Abstract

Stimulus-secretion coupling (SSC) of pancreatic islet cells comprises electrical activity. Changes of the membrane potential (Vm) are regulated by metabolism-dependent alterations in ion channel activity. This coupling is best explored in β cells. The effect of glucose is directly linked to mitochondrial metabolism as the ATP/ADP ratio determines the open probability of ATP-sensitive K+ channels (KATP channels). Nucleotide sensitivity and concentration in the direct vicinity of the channels are controlled by several factors including phospholipids, fatty acids, and kinases, e.g., creatine and adenylate kinase. Closure of KATP channels leads to depolarization of β cells via a yet unknown depolarizing current. Ca2+ influx during action potentials (APs) results in an increase of the cytosolic Ca2+ concentration ([Ca 2+ ] c) that triggers exocytosis. APs are elicited by opening of voltage-dependent Na + and/or Ca 2+ channels and repolarized by voltage- and/or Ca 2+ -dependent K + channels. At a constant stimulatory glucose concentration, APs are clustered in bursts that are interrupted by hyperpolarized interburst phases. Bursting electrical activity induces parallel fluctuations in [Ca2+] c and insulin secretion. Bursts are terminated by IksIow consisting of currents through Ca 2+ -dependent K + channels and KATP channels. This chapter focuses on structure, characteristics, physiological function, and regulation of ion channels in β cells. Information about pharmacological drugs acting on KATP channels, KATP channelopathies, and influence of oxidative stress on KATP channel function is provided. One focus is the outstanding significance of L-type Ca 2+ channels for insulin secretion. The role of less well-characterized β cell channels including voltage-dependent Na + channels, volume-sensitive anion channels (VSACs), transient receptor potential (TRP)-related channels, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is discussed. A model of β cell oscillations provides insight in the interplay of the different channels to induce and maintain electrical activity. Regulation of β cell electrical activity by hormones and the autonomous nervous system is discussed. α and δ cells are also equipped with K ATP channels and voltage-dependent Na +, K +, and Ca 2+ channels. Yet the SSC of these cells is less clear and is not necessarily dependent on K ATP channel closure. Different ion channels of α and δ cells are introduced and SSC in α cells is described with special respect to paracrine effects of insulin and GABA secreted from β cells.