critical role of gap junction coupled katp channel activity for regulated insulin secretion关键作用的间隙连接耦合通道活动诱导调控胰岛素分泌.pdfVIP

PLoS BIOLOGY Critical Role of Gap Junction Coupled KATP Channel Activity for Regulated Insulin Secretion 1 2 1 1 2 2* Jonathan V. Rocheleau , Maria S. Remedi , Butch Granada , W. Steven Head , Joseph C. Koster , Colin G. Nichols , 1* David W. Piston 1 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America, 2 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America Pancreatic b-cells secrete insulin in response to closure of ATP-sensitive Kþ (KATP) channels, which causes membrane depolarization and a concomitant rise in intracellular Ca2þ (Ca ). In intact islets, b-cells are coupled by gap junctions, i 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 b-cells from transgenic mice that express zero functional KATP channels in approximately 70% of their b-cells, but normal KATP channel density in the remainder. We found that KATP channel activity from approximately 30% of the b-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