S SLC24A Family (K + -Dependent Na + -Ca 2+ Exchanger, NCKX) Ali H. Jalloul 1 , Robert T. Szerencsei 1 , Tatiana P. Rogasevskaia 1,2 and Paul P.M. Schnetkamp 1 1 Department of Physiology & Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada 2 Department of Biology, Mount Royal University, Calgary, AB, Canada Synonyms K + -dependent Na + /Ca 2+ exchanger; Na + /Ca 2+ -K + exchanger; NCKX; Potassium-dependent sodium/calcium exchanger; Sodium/calcium- potassium exchanger; Solute carrier 24A gene family Historical Background Tightly controlled changes in cytosolic free Ca 2+ concentration are widely involved in cell signal- ing in most tissues of our body. Free Ca 2+ con- centration is increased through the activation of a wide range of surface or intracellular Ca 2+ chan- nels and is returned to resting values through the action of ATP-driven Ca 2+ pumps located in the plasma membrane and endoplasmic reticulum as well as Na + /Ca 2+ exchangers located on the plasma membrane. By the mid 1980s, it had been established that the surface membrane of the outer segments of retinal rod photoreceptors (ROS) contained a potent Na + -Ca 2+ exchange mechanism (Schnetkamp 1980; Yau and Nakatani 1984), and, in 1988, the Na + -Ca 2+ exchanger pro- tein was purified from bovine ROS as a 220 kDa glycoprotein (Cook and Kaupp 1988). In 1989, it was discovered that Na + -Ca 2+ exchange in ROS was a K + -dependent Na + /Ca 2+ exchange process operating at a stoichiometry of four Na + ions exchanged against one Ca 2+ plus one K + ion. This ion exchanger protein is now referred to as NCKX1 (Cervetto et al. 1989; Schnetkamp et al. 1989). In the early 1990s, the functional proper- ties and physiological role of the NCKX1 exchanger in ROS were examined in significant detail as described below, and, to date, these remain the only detailed studies of NCKX func- tion and physiology in native tissues. In 1992, the cDNA of the full-length bovine ROS NCKX was cloned and shown to encode a protein of 1,199 amino acids (Reiländer et al. 1992). In subsequent years, four additional and distinct human genes were identified encoding the NCKX2–5 proteins (Schnetkamp 2013). We now know that genes encoding NCKX proteins belong to the CaCA superfamily of cation/Ca 2+ exchangers and their closest relatives in the superfamily are the Na + /Ca 2+ exchanger (NCX) proteins carrying out K + -independent Na + /Ca 2+ exchange and stud- ied extensively in cardiomyocytes: the SLC24 # Springer Science+Business Media LLC 2017 S. Choi (ed.), Encyclopedia of Signaling Molecules, DOI 10.1007/978-1-4614-6438-9_101860-1