Role of Voltage-Dependent Na + Channels for Rhythmic Ca 2+ Signalling in Glucose-Stimulated Mouse Pancreatic β-Cells

Abstract

The putative role of voltage-dependent Na + channels for glucose induction of rhythmic Ca 2+ signalling was studied in mouse pancreatic β-cells with the use of the Ca 2+ indicator fura-2. A rise in glucose from 3 to 11 mM resulted in slow oscillations of the cytoplasmic Ca 2+ concentration ([Ca 2+] i). These oscillations, as well as superimposed transients seen during forskolin-induced elevation of cAMP, remained unaffected in the presence of the Na + channel blocker tetrodotoxin. During exposure to 1–10 μM veratridine, which facilitates the opening of voltage-dependent Na + channels, the slow oscillations were replaced by repetitive and pronounced [Ca 2+] i transients arising from the basal level. The effects of veratridine were reversed by tetrodotoxin. The veratridine-induced [Ca 2+] i transients were critically dependent on the influx of Ca 2+ and persisted after thapsigargin inhibition of the endoplasmic reticulum Ca 2+-ATPase. Both tolbutamide and ketoisocaproate mimicked the action of glucose in promoting [Ca 2+] i transients in the presence of veratridine. It is suggested that activation of voltage-dependent Na + channels is a useful approach for amplifying Ca 2+ signals for insulin release.