Electrophysiology of Islet Cells

Abstract

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. Ca(2+) influx during action potentials (APs) results in an increase of the cytosolic Ca(2+) concentration ([Ca(2+)](c)) that triggers exocytosis. APs are elicited by the 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 [Ca(2+)](c) and insulin secretion. Bursts are terminated by I(Kslow) consisting of currents through Ca(2+)-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 Ca(2+) 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. Regulation of beta-cell electrical activity by hormones and the autonomous nervous system is discussed. alpha- and delta-cells are also equipped with K(ATP) channels, 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 alpha- and delta-cells are introduced and SSC in alpha-cells is described in special respect of paracrine effects of insulin and GABA secreted from beta-cells.

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

“…Insulin secretion terminates when the b-cell is repolarized by the opening of potassium channels including members of the voltage-and calcium-activated potassium channel families. 24,25 Thus, the amount of insulin secreted is directly coupled to the electrical spiking activity of the b-cells, and each potassium channel involved in the repolarizing phase of spike plays a regulatory role in glucose-induced insulin release.…”

The Pancreatic β-Cell: A Bioenergetic Perspective

“…Electrophysiology has revealed a wealth of Na ϩ , Ca 2ϩ , and K ϩ ion channels on the ␤-cell plasma membrane with distinctive activation and inactivation kinetics responsible for the complex oscillatory behavior of the plasma membrane potential once the dominant K ATP channel is inhibited (64,133,452). There is persuasive evidence that the frequency and magnitude of these oscillations are central to understanding the control of insulin secretion, since oscillations, as well as first phase release, are defective in T2D (393).…”

GW9508 inhibits insulin secretion by activating ATP-sensitive potassium channels in rat pancreatic β-cells

“…The K ATP channel is a key controller to b-cell excitability and GSIS. It is known that pancreatic b-cells metabolize glucose to generate ATP from ADP, and the increased ATP:ADP ratio closes K ATP channels and leads to membrane depolarization and a concomitant rise in the levels of intracellular Ca 2C concentration ([Ca 2C ] i ) and insulin secretion (Ashcroft et al 1994, Rorsman 1997, Drews et al 2010, Rorsman et al 2011. In the present study, we further investigated the effects of GW9508 on insulin secretion, K ATP channels, and [Ca 2C ] i levels in primary rat islets and b-cells.…”