A ROLE FOR CA2-SENSITIVE NONSELECTIVE CATION CHANNELS IN REGULATING THE MEMBRANE-POTENTIAL OF PANCREATIC BETA-CELLS()

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 pancrea tic beta-cells and insulinoma cells. This MTX-sensitive current is pre sent in human beta-cells as men as in mouse and rat beta-cells, and is accompanied by a rise in cytosolic Ca2+ in voltage-clamped cells in w hich the activation of voltage-dependent Ca2+ channels is prevented. A ctivation of the nonselective cation current is inhibited by reduction of disulfide bonds with intracellular, but not extracellular, dithiot hreitol, and is also abolished by intracellular dialysis with trypsin. The nonselective cation channels that carry this current have a condu ctance of about 30 pS, with Na+ as the major extracellular cation. We estimate that these cation channels are expressed on beta-cells at a d ensity similar to that of ATP-sensitive potassium channels (K-ATP chan nels) 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 pot ential of beta-cells.