Role of Na/Ca Exchange and the Plasma Membrane Ca 2+ –ATPase in  Cell Function and Death ANDR ´ E HERCHUELZ, ADAMA KAMAGATE, HELENA XIMENES, AND FRANC ¸OISE VAN EYLEN Laboratory of Pharmacology, Brussels University School of Medicine, B-1070, Brussels, Belgium ABSTRACT: Recent progresses concerning the Na/Ca exchanger (NCX) and the plasma membrane Ca 2+ –ATPase (PMCA) in the pancreatic  cell are reviewed. The rat  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 ev- idence 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  cell. In contrast, overexpression of the PMCA markedly reduced the global rise in Ca 2+ induced by membrane depolar- ization, indicating that the PMCA has a capacity higher than expected to extrude Ca 2+ . Glucose, the main physiological stimulus of insulin release from the  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  cell switches from a low-efficiency Ca 2+ extruding mecha- nism, 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. KEYWORDS: sodium–calcium exchange; Na/Ca exchange; plasma mem- brane; Ca 2+ –ATPase; calcium; Ca 2+ ; PMCA Address for correspondence: Andr´ e Herchuelz, Laboratoire de Pharmacodynamie et de Th´ erapeutique, Universit´ e Libre de Bruxelles, Facult´ e de M´ edecine, Route de Lennik, 808-Bˆ atiment GE, B-1070 Bruxelles, Belgium. Voice: 32-2-555-62-01; fax: 32-2-555-63-70. herchu@ulb.ac.be Ann. N.Y. Acad. Sci. 1099: 456–467 (2007). C  2007 New York Academy of Sciences. doi: 10.1196/annals.1387.048 456