A role for Ca2+-sensitive nonselective cation channels in regulating the membrane potential of pancreatic beta-cells.

Abstract

The incretin hormones, glucagon-like peptide 1 and pituitary adenylyl cyclase-activating polypeptide, are proposed to activate a maitotoxin (MTX)-sensitive, Ca2+-dependent nonselective cation current in pancreatic beta-cells and insulinoma cells. This MTX-sensitive current is present in human beta-cells as well as in mouse and rat beta-cells, and is accompanied by a rise in cytosolic Ca2+ in voltage-clamped cells in which the activation of voltage-dependent Ca2+ channels is prevented. Activation of the nonselective cation current is inhibited by reduction of disulfide bonds with intracellular, but not extracellular, dithiothreitol, and is also abolished by intracellular dialysis with trypsin. The nonselective cation channels that carry this current have a conductance of about 30 pS, with Na+ as the major extracellular cation. We estimate that these cation channels are expressed on beta-cells at a density similar to that of ATP-sensitive potassium channels (K(ATP) channels) and exhibit spontaneous activity at basal glucose concentrations. We propose that this spontaneous cation channel activity constitutes at least part of the depolarizing background conductance that permits changes in the activity of K(ATP) channels to regulate the resting potential of beta-cells.

Unregulated Insulin Secretion by Pancreatic Beta Cells in Hyperinsulinism/Hyperammonemia Syndrome: Role of Glutamate Dehydrogenase, ATP-Sensitive Potassium Channel, and Nonselective Cation Channel

“…The currents of MIN6 cells were decreased by an NSCC blocker, GdCl 3 ( Fig. 5B) and activated by an NSCC activator, maitotoxin (16). The GdCl 3 -and maitotoxin-sensitive current had a reversal potential of Ϫ6.6 Ϯ 1.5 mV (n ϭ 10) and thus was most likely an NSCC current.…”

A TRP channel contributes to insulin secretion by pancreatic β-cells

“…6 These channels are characterized by a conductance of 20-25 pS and sensitivity to block by adenine nucleotides. A link between these channels and insulin secretion has been suggested by experiments showing that in β-cells the insulinotropic hormone, glucagon-like peptide-1a activates a nonselective conductance sensitive to Ca 2+ and cAMP 7,8 and that release of Ca 2+ from intracellular stores activates a conductance sensitive to maitoxin, a toxin that promotes insulin release. 9 Until now, the molecular identity of these Ca-NS channels was unknown.…”

Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review]

“…The triggering pathway is followed by time-dependent increase in insulin secretion that is potentiated by glucose exposure (the second phase, potentiating pathway or KATP-independent pathway) [3,8] However, closure of the KATP channel alone is not sufficient to induce a shift in the membrane potential towards the threshold level and for the triggering pathway that can activate VDCCs, since membrane potential is theoretically determined by the overall balance of outward and inward currents. Modest background inward currents through opening of nonselective cation channels (NSCCs) are crucial for induction of membrane depolarization following KATP channel closure [9,10]. This idea further suggests that regulation of a class of NSCCs may play an important role in producing effective depolarization of the membrane.…”