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...

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Published inMathematical 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
LanguageEnglish
Published United States 29.05.2024
Subjects
Computational modeling
β-cells
Gap junctions
Pancreatic islets
Ca(2+) imaging
Diabetes
Gene expression
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Summary: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 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 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 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 oscillations.
ISSN:1879-3134