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

Abstract

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 β-cells of mouse pancreatic islets exposed to elevated glucose. In 11.1 m m glucose, the non-peptidyl BK channel blocker paxilline increased the height of β-cell action potentials (APs) by 21 mV without affecting burst- or silent-period durations. In isolated β-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 Ca 2+ channel blockers Cd 2+ (200 μ m ) or nimodipine (1 μ m ), and potentiated by FPL-64176 (1 μ m ). I BK was also 56% blocked by the BK channel blocker iberiotoxin (100 n m ). 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 m m glucose plus paxilline, activated 4-fold more I Kv and significantly increased Ca 2+ entry. Paxilline increased insulin secretion in islets exposed to 11.1 m m glucose by 67%, but did not affect basal secretion in 2.8 m m glucose. These data suggest a modified model of β-cell AP generation where I BK and I Kv coordinate the AP repolarisation.