NA+ CA2+ EXCHANGE AND CELLULAR CA2+ HOMEOSTASIS/

The Na+/Ca2+ exchange system is the primary Ca2+ efflux mechanism in c ardiac myocytes, and plays an important role in controlling the force of cardiac contraction. The exchanger protein contains 11 transmembran e segments plus a large hydrophilic domain between the 5th and 6th tra nsmembrane segments; the transmembrane regions are reponsible for medi ating ion translocation while the hydrophilic domain is responsible fo r regulation of activity. Exchange activity is regulated in vitro by i nterconversions between an active state and either of two inactive sta tes. High concentrations of cytosolic Nat or the absence of cytosolic Ca2+ promote the formation of the inactive states; phosphatidylinosito l-(4,5)bisphosphate (or other negatively charged phospholipids) and cy tosolic Ca2+ counteract the inactivation process. The importance of th ese mechanisms in regulating exchange activity under normal physiologi cal conditions is uncertain. Exchanger function is also dependent upon cytoskeletal interactions, and the exchanger's location with respect to intracellular Ca2+-sequestering organelles. An understanding of the exchanger's function in normal cell physiology will require more deta iled information on the proximity of the exchanger and other Ca2+-tran sporting proteins, their interactions with the cytoskeleton, and local concentrations of anionic phospholipids and transported ions.