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

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Abstract

We studied the effect of gap junctional coupling on the excitability of beta-cells in slices of pancreas, which provide a normal environment for islet cells. The electrophysiological properties of beta-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 beta-cells were found to be unchanged after the knockout of Cx36, except the density of Ca(2+) channels, which was increased in uncoupled cells. With closed ATP-sensitive K(+) (K(ATP)) channels, the electrically coupled beta-cells of Cx36(+/+) and Cx36(+/-) mice were hyperpolarized by the membrane potential of adjacent, inactive cells. Additionally, the hyperpolarization of one beta-cell could attenuate or even stop the electrical activity of nearby coupled cells. In contrast, beta-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 beta-cells consistent with the reported increase in basal insulin release and altered the switch on/off response of beta-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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