Metabolic Stress Shifts the Function of KCa3.1 Channels in Pancreatic Beta Cells From a Regulator of Membrane Potential to a Proapoptotic Factor.

Metabolic stress increases the whole-cell current through KCa3.1 channels in mouse pancreatic islet cells. The study aimed to analyze the network between ion channels mediating Ca2+ influx for KCa3.1 channel activation and stress-related changes. The physiologically important Kslow current of beta cells was not altered in total but the contribution of KCa3.1 current was reduced after culture in the presence of high glucose and palmitate concentrations. Electrical activity was increased by blocking KCa3.1 channels with senicapoc in islets cultured under standard conditions but not after metabolic stress. Of note, the functional coupling of KCa3.1 to l-type Ca2+ channels was severely reduced by metabolic stress, whereas the coupling to Ca2+-influx via NMDA receptors increased. Mitochondrial membrane potential of beta cells was not affected by senicapoc but by a mitochondria-targeted derivative. Inhibition of KCa3.1 channels by senicapoc or maurotoxin partly protected from apoptosis. In conclusion, the data indicate a shift in the interplay of Ca2+-conducting ion channels and the plasma membrane-localized KCa3.1 channel. KCa3.1 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.