Françoise Van Eylen

Role of Na/Ca Exchange and the Plasma Membrane Ca2+–ATPase in β Cell Function and Death

Abstract:  Recent progresses concerning the Na/Ca exchanger (NCX) and the plasma membrane Ca2+–ATPase (PMCA) in the pancreatic β cell are reviewed. The rat β cell expresses two splice variants of NCX1 and six splice variants of the 4 PMCA isoforms. At the protein level, the most abundant forms are PMCA2 and PMCA3, providing the first evidence for the presence of these two isoforms in a non‐neuronal tissue. Overexpression of NCX1 in an insulinoma cell line altered the initial rise in cytosolic‐free Ca2+ concentration ([Ca2+]i) induced by membrane depolarization and the return of the [Ca2+]i to the baseline value on membrane repolarization, indicating that NCX contributes to both Ca2+ inflow and outflow in the β cell. In contrast, overexpression of the PMCA markedly reduced the global rise in Ca2+ induced by membrane depolarization, indicating that the PMCA has a capacity higher than expected to extrude Ca2+. Glucose, the main physiological stimulus of insulin release from the β cell, has opposite effect on NCX and PMCA transcription, expression and activity, inducing an increase in the case of NCX and a decrease in the case of the PMCA. This indicates that when exposed to glucose, the β cell switches from a low‐efficiency Ca2+ extruding mechanism, the PMCA, to a high‐capacity system, the NCX, in order to better face the increase in Ca2+ inflow induced by the sugar. To our knowledge, this is the first demonstration of a reciprocal change in PMCA and NCX1 expression and activity in response to a given stimulus in any tissue.

Inhibition of Na/Ca exchange stimulates insulin release from isolated rat pancreatic islets

Summary— Na/Ca exchange was recently shown to regulate cytosolic free Ca2+ concentration ([Ca2+]i) in the pancreatic B‐cell. The aim of the present study was to provide direct evidence that inhibition of the activity of the exchange may also increase insulin release. In the presence of extracellular Na+, caffeine stimulated 45Ca outflow but did not increase insulin release from islets perifused in the presence of 2.8 mM glucose. By contrast, in the absence of extracellular Na+, caffeine almost failed to increase 45Ca outflow and reversibly stimulated insulin release despite the fact that the absence of extracellular Na+ per se reduced basal insulin release. Similar findings were observed in islets perifused at a higher glucose concentration (8.3 mM) except that, in the presence of extracellular Na+, caffeine more markedly increased 45Ca outflow and stimulated insulin release. Our data provide direct evidence that inhibition of Na/Ca exchange with resulting blockade of Ca2+ outflow may increase insulin release from the pancreatic B‐cell under suitable experimental conditions.

Na/Ca Exchange in Function, Growth, and Demise of β-Cells

Abstract: Recent knowledge concerning the Na/Ca exchanger (NCX) in the pancreatic β‐cell is reviewed. The β‐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) and in variable and different proportions. In the rat β‐cell, the exchanger displays a high capacity, accounts for about 70% of Ca2+ extrusion, and participates in 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 β‐cell electrical activity and intracellular Ca2+ oscillations. Intracellular Ca2+ may also trigger apoptosis. For instance, overexpression of the exchanger increases Ca2+‐dependent and Ca2+‐independent β‐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 β‐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 β‐cell.