Significance of Na/Ca exchange for Ca2+ buffering and electrical activity in mouse pancreatic β-cells

We have combined the patch-clamp technique with microfluorimetry of the cytoplasmic Ca2+ concentration ([Ca2+](i)) to characterize Na/Ca exchange in mouse beta-cells and to determine its importance for [Ca2+](i) buffering and shaping of glucose-induced electrical activity. The exchanger contributes to Ca2+ removal at [Ca2+](i) above 1 mu M, where it accounts for >35% of the total removal rate. At lower [Ca2+](i), thapsigargin-sensitive Ca2+-ATPases constitute a major (70% at 0.8 mu M [Ca2+](i)) mechanism for Ca2+ removal. The beta-cell Na/Ca exchanger is electrogenic and has a stoichiometry of three Na+ for one Ca2+, The current arising from its operation reverses at similar to-20 mV (current inward at more negative voltages), has a conductance of 53 pS/pF;(14 mu M [Ca2+](i)), and is abolished by removal of external Na+ or by intracellularly applied XIP (exchange inhibitory peptide). Inhibition of the exchanger results in shortening: (50%) of the bursts of action potentials of glucose-stimulated beta-cells in intact islets and a slight (5 mV) hyperpolarization. Mathematical simulations suggest that the stimulatory action of glucose on beta-cell electrical activity may be accounted for in part by glucose-induced reduction of the cytoplasmic Na+ concentration with resultant activation of the exchanger.