Sodium/potassium/calcium exchanger family is also known as solute carrier family 24. Members of the SLC24 gene family encode K+-dependent Na+-Ca2+ exchangers (NCKX) which utilize both the inward Na+ and outward K+ gradients to extrude Ca2+ from cells. There are five human SLC24 genes that play a role in biological processes such as vision in retinal rod and cone photoreceptors, olfaction, skin pigmentation and at least three of the five genes are also widely expressed in the brain. Like most other solute carriers, NCKX transporters are thought to play roles via the alternating access mechanism.
Fig.1 Current topological model of NCKX proteins. (Schnetkamp, 2013)
For NCKX1 in ROS as well for NCKX2 expressed in cell lines, the transport stoichiometry was determined to be 4Na+:(1Ca2++1K+). This means that Ca2+ extrusion from cells is driven by both inward Na+ and outward K+ gradients and is also driven by the negative inside membrane potential in view of the electrogenic nature of transport. This also means that Na+/Ca2+-K+ exchangers can maintain larger Ca2+ gradients than the NCX Na+/Ca2+ exchangers operating at a 3:1 stoichiometry. In addition, Na+/Ca2+-K+ exchangers do not easily reverse from the Ca2+ efflux mode to Ca2+ influx mode upon strong membrane depolarization and/or reduction of the transmembrane Na+ gradient when compared with the Na+/Ca2+ exchanger. This would make NCKX proteins a preferred choice for cells exhibiting long-lived depolarizations due to sustained inward Na+ currents which are likely to decrease the transmembrane Na+ gradient as well, thereby reducing two of the three components of the driving force to extrude Ca2+ from cells via NC(K)X exchangers. This applies to the retinal rod and cone photoreceptors, both of which operate by modulating a sustained inward Na+ and Ca2+ current carried by cGMP-gated channels.
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