Electrophysiology of Islet Cells

Stimulus-Secretion Coupling (SSC) of pancreatic islet cells comprises electrical activity. Changes of the membrane potential (V-m) are regulated by metabolism-dependent alterations in ion channel activity. This coupling is best explored in beta-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 (K-ATP 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 K-ATP channels leads to depolarization of beta-cells via a yet unknown depolarizing current. Ca2+ influx during action potentials (APs) results in an increase of the cytosolic Ca2+ concentration ([Ca2+](c)) that triggers exocytosis. APs are elicited by the opening of voltage-dependent Na+ and/or Ca2+ channels and repolarized by voltage- and/or Ca2+-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 I-Kslow consisting of currents through Ca2+-dependent K+ channels and K-ATP channels. This review focuses on structure, characteristics, physiological function, and regulation of ion channels in beta-cells. Information about pharmacological drugs acting on K-ATP channels, K-ATP channelopathies, and influence of oxidative stress on K-ATP channel function is provided. One focus is the outstanding significance of L-type Ca2+ channels for insulin secretion. The role of less well characterized beta-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 beta-cell oscillations provides insight in the interplay of the different channels to induce and maintain electrical activity.