title: 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 mM 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 μM) or nimodipine (1 μM), and potentiated by FPL-64176 (1 μM). 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 Ca(2+) 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 β-cell AP generation where I(BK) and I(Kv) coordinate the AP repolarisation.
authors.affiliation: Department of Pharmacology and Brehm Diabetes Center, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
authors.forename: Khaled M
authors.initials: KM
authors.lastname: Houamed
authors.forename: Ian R
authors.initials: IR
authors.lastname: Sweet
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane; D002478:Cells, Cultured; D055724:Electrophysiological Phenomena / Q000502:physiology*; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D013997:Time Factors
chemical_list: D007328:Insulin; D051036:Large-Conductance Calcium-Activated Potassium Channels; D005947:Glucose; D002118:Calcium