Electrical activity in pancreatic islet cells: The VRAC hypothesis

Abstract

A major aspect of stimulation of β-cell function by glucose is the induction of electrical activity. The ionic events that underlie β-cell electrical activity are understood in some detail. At sub-stimulatory glucose concentrations, the β-cell is electrically 'silent'. Increasing the glucose concentration to stimulatory levels results in a gradual depolarisation of the membrane potential to a threshold potential where 'spikes' or action potentials are generated. These action potentials represent the gating of voltage-sensitive Ca²(+) channels, leading to Ca²(+) entry into the cell, thus triggering the release of insulin. The stimulatory actions of glucose on the β-cell depend on the metabolism of the hexose. A major question concerns the molecular mechanism(s) whereby β-cell plasma membrane potential is regulated by changes in glucose metabolism in the cell. This article provides a brief summary of the evidence suggesting that, in addition to metabolically-regulated K(ATP) channels, β-cells are equipped with a volume-regulated anion channel that is activated by glucose concentrations within the range effective in modulating electrical activity and insulin release.

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

“…Glucose still induces electrical activity and insulin secretion even when K ATP channels are inactivated (24,25,35,36). Chloride levels in β cells are known to be important for insulin secretion, and chloride channel(s) have been proposed as part of the background channels contributing to the regulation of electrical activity and insulin secretion in β cells, although the identity of such a channel remains elusive (24,25). It has been reported that ANO1 knockdown reduces chloride ion transport in diverse cell types (37), although islets have not been studied.…”

“…Glucose increases chloride efflux in β cells, which could contribute to membrane depolarization (20)(21)(22)(23). Although the identity of the chloride channel(s) in β cells remains unclear, it has been proposed that certain unidentified chloride channels expressed in the plasma membrane might be involved in the regulation of electrical activity and insulin secretion in β cells (24,25). Because glucose quickly increases ANO1 gene expression, we investigated whether ANO1, the membrane calciumactivated chloride channel gene known to be expressed at a significant level in human islets (Fig.…”

“…S1). ANO1 is a calcium-activated chloride channel protein (17)(18)(19); chloride ion levels in β cells are known to influence insulin secretion (20)(21)(22)(23), and it has been proposed that one or more chloride channels contribute to the regulation of plasma membrane electrical activity and insulin secretion in β cells (24,25). ANO1 protein and its closest homolog ANO2 are expressed mainly in the plasma membrane and act as membrane calcium-activated chloride channels (17)(18)(19), but whether other members of the ANO family are also plasma membrane chloride channels in vivo remains unclear (26,27).…”

Effects of octane derivatives on activity of the volume-regulated anion channel in rat pancreatic β-cells

“…Briefly, VRAC activation results in Cl -efflux generating an inward (depolarizing) current. Glucose and several stimuli of b-cell function have been shown to activate the conductance, possibly as a result of increased b-cell volume [4,6]. VRAC activation could subsequently contribute towards electrical and secretory activity.…”

“…The effects of FFAs consisted of an initial enhancement and subsequent suppression of glucose-induced electrical activity, and were attributed predominantly to the activation, followed by an inhibition, of the volume-regulated anion channel (VRAC). The putative role of this conductance in the pancreatic b-cell has been reviewed elsewhere [4,6]. Briefly, VRAC activation results in Cl -efflux generating an inward (depolarizing) current.…”