Role of Na/Ca Exchange and the Plasma Membrane Ca 2+ –ATPase in β Cell Function and Death

 Recent progresses concerning the Na/Ca exchanger (NCX) and the plasma membrane Ca 2+ –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 Ca 2+ concentration ([Ca 2+ ] i ) induced by membrane depolarization and the return of the [Ca 2+ ] i to the baseline value on membrane repolarization, indicating that NCX contributes to both Ca 2+ inflow and outflow in the β cell. In contrast, overexpression of the PMCA markedly reduced the global rise in Ca 2+ induced by membrane depolarization, indicating that the PMCA has a capacity higher than expected to extrude Ca 2+ . 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 Ca 2+ extruding mechanism, the PMCA, to a high‐capacity system, the NCX, in order to better face the increase in Ca 2+ 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.