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

Murat An, Mesut Akyuz, Ozel Capik, Cigdem Yalcin, Richard Bertram, Elanur Aydin Karatas, Omer Faruk Karatas, Vehpi Yildirim*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number109224
JournalMathematical Biosciences
Volume374
DOIs
Publication statusPublished - Aug 2024

Bibliographical note

Publisher Copyright: © 2024

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this