Gain of Function Mutation in K(Atp) Channels and Resulting Upregulation of Coupling Conductance Are Partners in Crime in the Impairment of Ca2+ Oscillations in Pancreatic B-Cells

Abstract

Gain of function mutations in the pore forming Kir6 subunits of the ATP sensitive K+ channels (K(ATP) channels) of pancreatic 8-cells are the major cause of neonatal diabetes in humans. In this study, we show that in insulin secreting mouse 8-cell lines, gain of function mutations in Kir6.1 result in a significant connexin36 (Cx36) overexpression, which form gap junctional connections and mediate electrical coupling between 8-cells within pancreatic islets. Using computational modeling, we show that upregulation in Cx36 might play a functional role in the impairment of glucose stimulated Ca2+ oscillations in a cluster of 8-cells with Kir6.1 gain of function mutations in their K(ATP) channels (GoF-K(ATP) channels). Our results show that without an increase in Cx36 expression, a gain of function mutation in Kir6.1 might not be sufficient to diminish glucose stimulated Ca2+ oscillations in a 8-cell cluster. We also show that a reduced Cx36 expression, which leads to loss of coordination in a wild-type 8-cell cluster, restores coordinated Ca2+ oscillations in a 8-cell cluster with GoF-K(ATP) channels. Our results indicate that in a heterogenous 8-cell cluster with GoF-K(ATP) channels, there is an inverted u-shaped nonmonotonic relation between the cluster activity and Cx36 expression. These results show that in a neonatal diabetic 8-cell model, gain of function mutations in the Kir6.1 cause Cx36 overexpression, which aggravates the impairment of glucose stimulated Ca2+ oscillations.