Critical role of gap junction coupled KATP channel activity for regulated insulin secretion

Jonathan V. Rocheleau, Maria S. Remedi, Butch Granada, W. Steven Head, Joseph C. Koster, Colin G. Nichols, David W. Piston

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

Pancreatic β-cells secrete insulin in response to closure of ATP-sensitive K+ (KATP) channels, which causes membrane depolarization and a concomitant rise in intracellular Ca2+ (Ca i). In intact islets, β-cells are coupled by gap junctions, which are proposed to synchronize electrical activity and Cai oscillations after exposure to stimulatory glucose (>7 mM). To determine the significance of this coupling in regulating insulin secretion, we examined islets and β-cells from transgenic mice that express zero functional K ATP channels in approximately 70% of their β-cells, but normal KATP channel density in the remainder. We found that KATP channel activity from approximately 30% of the β-cells is sufficient to maintain strong glucose dependence of metabolism, Cai, membrane potential, and insulin secretion from intact islets, but that glucose dependence is lost in isolated transgenic cells. Further, inhibition of gap junctions caused loss of glucose sensitivity specifically in transgenic islets. These data demonstrate a critical role of gap junctional coupling of KATP channel activity in control of membrane potential across the islet. Control via coupling lessens the effects of cell-cell variation and provides resistance to defects in excitability that would otherwise lead to a profound diabetic state, such as occurs in persistent neonatal diabetes mellitus. Copyright:

Original languageEnglish
Pages (from-to)221-227
Number of pages7
JournalPLoS biology
Volume4
Issue number2
DOIs
StatePublished - Feb 1 2006

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