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

We studied the effect of gap junctional coupling on the excitability of -cells in slices of pancreas, which provide a normal environment for islet cells. The electrophysiological properties of -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 -cells were found to be unchanged after the knockout of Cx36, except the density of Ca channels, which was increased in uncoupled cells. With closed ATP-sensitive K (KATP) channels, the electrically coupled -cells of Cx36 / and Cx36 / mice were hyperpolarized by the membrane potential of adjacent, inactive cells. Additionally, the hyperpolarization of one -cell could attenuate or even stop the electrical activity of nearby coupled cells. In contrast, -cells of Cx36 / littermates with blocked KATP channels rapidly depolarized and exhibited a continuous electrical activity. Absence of electrical coupling modified the electrophysiological properties of -cells consistent with the reported increase in basal insulin release and altered the switch on/off response of -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. Diabetes 56:1078–1086, 2007