Metabolic Stress Shifts the Function of K Ca 3.1 Channels in Pancreatic Beta Cells From a Regulator of Membrane Potential to a Proapoptotic Factor

ABSTRACT Metabolic stress increases the whole‐cell current through K Ca 3.1 channels in mouse pancreatic islet cells. The study aimed to analyze the network between ion channels mediating Ca 2+ influx for K Ca 3.1 channel activation and stress‐related changes. The physiologically important K slow current of beta cells was not altered in total but the contribution of K Ca 3.1 current was reduced after culture in the presence of high glucose and palmitate concentrations. Electrical activity was increased by blocking K Ca 3.1 channels with senicapoc in islets cultured under standard conditions but not after metabolic stress. Of note, the functional coupling of K Ca 3.1 to l ‐type Ca 2+ channels was severely reduced by metabolic stress, whereas the coupling to Ca 2+ ‐influx via NMDA receptors increased. Mitochondrial membrane potential of beta cells was not affected by senicapoc but by a mitochondria‐targeted derivative. Inhibition of K Ca 3.1 channels by senicapoc or maurotoxin partly protected from apoptosis. In conclusion, the data indicate a shift in the interplay of Ca 2+ ‐conducting ion channels and the plasma membrane‐localized K Ca 3.1 channel. K Ca 3.1 channels changed from an important regulator of membrane potential oscillations to a dysfunctional and proapoptotic factor. This switch might be involved in the decline of islet cell mass and function during progression of type 2 diabetes mellitus.