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Cx36-Mediated Coupling Reduces ß-Cell Heterogeneity, Confines the Stimulating Glucose Concentration Range, and Affects Insulin Release Kinetics

¹ Neuroendocrinology, European Neuroscience Institute Göttingen, Göttingen, Germany
² Department of Cell Physiology and Metabolism, University of Geneva, Genève, Switzerland

Address correspondence and reprint requests to Stephan Speier, The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital L1, Stockholm, Sweden. E-mail: stephan.speier{at}ki.se

Abbreviations: Cx36, connexin36; K_ATP channel, ATP-sensitive K⁺ channel

We studied the effect of gap junctional coupling on the excitability of ß-cells in slices of pancreas, which provide a normal environment for islet cells. The electrophysiological properties of ß-cells from mice (C57Bl/6 background) lacking the gap junction protein connexin36 (Cx36^–/–) were compared with heterozygous (Cx36^+/–) and wild-type littermates (Cx36^+/+) and with frequently used wild-type NMRI mice. Most electrophysiological characteristics of ß-cells were found to be unchanged after the knockout of Cx36, except the density of Ca²⁺ channels, which was increased in uncoupled cells. With closed ATP-sensitive K⁺ (K_ATP) channels, the electrically coupled ß-cells of Cx36^+/+ and Cx36^+/– mice were hyperpolarized by the membrane potential of adjacent, inactive cells. Additionally, the hyperpolarization of one ß-cell could attenuate or even stop the electrical activity of nearby coupled cells. In contrast, ß-cells of Cx36^–/– littermates with blocked K_ATP channels rapidly depolarized and exhibited a continuous electrical activity. Absence of electrical coupling modified the electrophysiological properties of ß-cells consistent with the reported increase in basal insulin release and altered the switch on/off response of ß-cells during an acute drop of the glucose concentration. Our data indicate an important role for Cx36-gap junctions in modulating stimulation threshold and kinetics of insulin release.

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