Getting a grip on calcium regulation

Temporally and spatially regulated Ca2+ signals control numerous physiological processes. In most cells in higher animals, the plasma membrane (PM) Na/Ca exchanger (NCX) helps manage the cytosolic Ca2+ concentration ([Ca2+]CYT) and Ca2+ stored in the sarco-/endoplasmic reticulum (S/ER), thereby influencing Ca2+ signaling (1–3). This tightly regulated transporter can move one Ca2+ ion either out of or into cells in exchange for three Na+. The direction of net Ca2+ movement depends on the prevailing membrane potential (V M) as well as the Na+ and Ca2+ concentration gradients because there is net charge transfer. Cardiac myocytes have large dynamic swings in V M and [Ca2+]CYT during each heartbeat, and NCX plays an especially interesting role: It can mediate Ca2+ entry during the upstroke of the action potential, help maintain the elevated [Ca2+]CYT and contraction during the action potential plateau, and then extrude Ca2+ during repolarization and diastole (1). It is noteworthy that NCX is regulated by cytosolic Na+ and Ca2+ at sites that do not directly participate in the ion translocation (4, 5). A rise in cytosolic Na+ rapidly stimulates and then inactivates the exchanger (6); in contrast, cytosolic Ca2+ activates the exchanger and relieves the Na+-dependent inactivation (4, 5). Two elegant studies by Philipson, Abramson, and colleagues, including one in this issue of PNAS (7), provide novel insight into how Ca2+ binds to and alters the conformation of the Ca2+ regulatory sites in the cardiac/neuronal NCX (NCX type-1) (7, 8).