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J Physiol. 2010 Sep 15;588(Pt 18):3511-23. doi: 10.1113/jphysiol.2009.184341. Epub 2010 Jul 19.

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

Author information

1
Department of Pharmacology and Brehm Diabetes Center, University of Michigan Medical School, Ann Arbor, MI 48105, USA.

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.

PMID:
20643769
PMCID:
PMC2988515
DOI:
10.1113/jphysiol.2009.184341
[Indexed for MEDLINE]
Free PMC Article

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