BK channels mediate a novel ionic mechanism that regulates glucose-dependent electrical activity and insulin secretion in mouse pancreatic β-cells

BK channels are large unitary conductance K+ channels cooperatively activated by intracellular calcium and membrane depolarisation. We show that BK channels regulate electrical activity in beta-cells of mouse pancreatic islets exposed to elevated glucose. In 11.1 mm glucose, the non-peptidyl BK channel blocker paxilline increased the height of beta-cell action potentials (APs) by 21 mV without affecting burst- or silent-period durations. In isolated beta-cells, paxilline increased AP height by 16 mV without affecting resting membrane potential. In voltage clamp, paxilline blocked a transient component of outward current activated by a short depolarisation, which accounted for at least 90% of the initial outward K+ current. This BK current (I-BK) was blocked by the Ca2+ channel blockers Cd2+ (200 mu m) or nimodipine (1 mu m), and potentiated by FPL-64176 (1 mu m). I-BK was also 56% blocked by the BK channel blocker iberiotoxin (100 nm). I-BK activated more than 10-fold faster than the delayed rectifier I-Kv over the physiological voltage range, and partially inactivated. An AP-like command revealed that I-BK activated and deactivated faster than I-Kv and accounted for 86% of peak I-K, explaining why I-BK block increased AP height. A higher amplitude AP-like command, patterned on an AP recorded in 11.1 mm glucose plus paxilline, activated 4-fold more I-Kv and significantly increased Ca2+ entry. Paxilline increased insulin secretion in islets exposed to 11.1 mm glucose by 67%, but did not affect basal secretion in 2.8 mm glucose. These data suggest a modified model of beta-cell AP generation where I-BK and I-Kv coordinate the AP repolarisation.