Na/Ca exchange and Ca2+ homeostasis in the pancreatic beta-cell

Recent knowledge concerning the Na/Ca exchanger (NCX) in the pancreatic beta-cell is reviewed. The beta-cell expresses various NCX1 splice variants in a species specific pattern (NCX1.3 and 1.7 in the rat, NCX1.2, 1.3 and 1.7 in the mouse), in variable and different proportions. In the rat beta-cell, the exchanger displays a quite high capacity, accounts for about 70% of Ca2+ extrusion and participates to Ca2+ inflow during membrane depolarization. In the mouse, however, the contribution of the exchanger to Ca2+ extrusion is more modest, and to Ca2+ inflow less evident. The exchanger has a stoichiometry of 3 Na+ for 1 Ca2+, is electrogenic, and displays a reversal potential at -20 mV. Although being of low magnitude, the current generated by the exchanger shapes glucose-induced beta-cell electrical activity and intracellular Ca2+ oscillations. For instance, a lower Na/Ca exchange activity (and subsequent inward current) in the mouse than in the rat, explains why the mouse beta-cell displays cyclic oscillations of the membrane potential, while the rat displays a staircase increase in membrane potential without such oscillations. In addition of being of importance in cell signalling, intracellular Ca2+ may also trigger apoptosis. For instance, overexpression of the exchanger increases Ca2+-dependent and -independent beta-cell death by apoptosis, a phenomenon resulting from the depletion of ER Ca2+-stores with subsequent activation of caspase-12. Na/Ca exchange overexpression also reduces beta-cell growth. Hence, the Na/Ca exchanger is a versatile system that appears to play an important role in the function, growth and demise of the beta-cell.