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 ß-cells

• Published in: Mathematical biosciences Vol. 374; p. 109224
• Main Authors: An, Murat, Akyuz, Mesut, Capik, Ozel, Yalcin, Cigdem, Bertram, Richard, Karatas, Elanur Aydin, Karatas, Omer Faruk, Yildirim, Vehpi
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2024
• Subjects: Ca2+ imaging; Computational modeling; Diabetes; Gap junctions; Gene expression; Pancreatic islets; β-cells; Computational modeling; β-cells; Gap junctions; Ca2+ imaging; Pancreatic islets; Diabetes; Gene expression
• ISSN: 0025-5564; 1879-3134; 1879-3134
• DOI: 10.1016/j.mbs.2024.109224

•In insulin secreting mouse β-cell lines, gain of function mutations in K(ATP) channels result in a significant connexin36 overexpression.•Increased connexin36 expression and resulting increase in gap-junctional conductance aggravates impairments in Ca2+ oscillations in a neonatal diabetic model β-cell cluster.•In β-cell clusters with increased K(ATP) conductance, there is an inverted U-shaped nonmonotonic relation between the cluster activity and the level of gap-junctional conductance.•Reduced connexin36 expression, which leads to loss of coordination in model wild-type β-cell clusters, restores coordinated Ca2+ oscillations in neonatal diabetic β-cell clusters. 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ oscillations.