Gain of function mutation in K(ATP) channels and resulting upregulation of coupling conductance are partners in crime in the impairment of Ca 2+ oscillations in pancreatic ß-cells.

Gain of function mutations in the pore forming Kir6 subunits of the ATP sensitive K ⁺ channels (K(ATP) channels) of pancreatic β-cells are the major cause of neonatal diabetes in humans. In this study, we show that in insulin secreting mouse β-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 β-cells within pancreatic islets. Using computational modeling, we show that upregulation in Cx36 might play a functional role in the impairment of glucose stimulated Ca ²⁺ oscillations in a cluster of β-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 Ca ²⁺ oscillations in a β-cell cluster. We also show that a reduced Cx36 expression, which leads to loss of coordination in a wild-type β-cell cluster, restores coordinated Ca ²⁺ oscillations in a β-cell cluster with GoF-K(ATP) channels. Our results indicate that in a heterogenous β-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 β-cell model, gain of function mutations in the Kir6.1 cause Cx36 overexpression, which aggravates the impairment of glucose stimulated Ca ²⁺ oscillations.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vehpi Yildirim reports financial support was provided by Scientific and Technological Research Council of Turkey. Richard Bertram reports financial support was provided by National Science Foundation. Co-authors Omer Faruk Karatas and Elanur Aydin Karatas hold stocks in EcoTech Biotechnology. The terms of this arrangement have been reviewed and approved by Erzurum Technical University in accordance with its policy on objectivity in research. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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