The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.

https://www.physiology.org/doi/pdf/10.1152/physrev.1999.79.3.763

Sodium/Calcium Exchange: Its Physiological Implications

Calcium ions are ubiquitous and versatile signaling molecules, capable of decoding a variety of extracellular stimuli (hormones, neurotransmitters, growth factors, etc.) into markedly different int...

https://www.physiology.org/doi/pdf/10.1152/physrev.00004.2005

Microdomains of intracellular Ca2+: molecular determinants and functional consequences.

Cation transport is a critical process in all organisms and is essential for mineral nutrition, ion stress tolerance, and signal transduction. Transporters that are members of the Ca(2+)/cation antiporter (CaCA) superfamily are involved in the transport of Ca(2+) and/or other cations using the counter exchange of another ion such as H(+) or Na(+). The CaCA superfamily has been previously divided into five transporter families: the YRBG, Na(+)/Ca(2+) exchanger (NCX), Na(+)/Ca(2+), K(+) exchanger (NCKX), H(+)/cation exchanger (CAX), and cation/Ca(2+) exchanger (CCX) families, which include the well-characterized NCX and CAX transporters. To examine the evolution of CaCA transporters within higher plants and the green plant lineage, CaCA genes were identified from the genomes of sequenced flowering plants, a bryophyte, lycophyte, and freshwater and marine algae, and compared with those from non-plant species. We found evidence of the expansion and increased diversity of flowering plant genes within the CAX and CCX families. Genes related to the NCX family are present in land plant though they encode distinct MHX homologs which probably have an altered transport function. In contrast, the NCX and NCKX genes which are absent in land plants have been retained in many species of algae, especially the marine algae, indicating that these organisms may share "animal-like" characteristics of Ca(2+) homeostasis and signaling. A group of genes encoding novel CAX-like proteins containing an EF-hand domain were identified from plants and selected algae but appeared to be lacking in any other species. Lack of functional data for most of the CaCA proteins make it impossible to reliably predict substrate specificity and function for many of the groups or individual proteins. The abundance and diversity of CaCA genes throughout all branches of life indicates the importance of this class of cation transporter, and that many transporters with novel functions are waiting to be discovered.

/pdf/protein-phylogenetic-analysis-of-ca2-cation-antiporters-and-40fvvxg8a3.pdf

Protein Phylogenetic Analysis of Ca2+/cation Antiporters and Insights into their Evolution in Plants

Mitochondrial Ca(2+) efflux is linked to numerous cellular activities and pathophysiological processes. Although it is established that an Na(+)-dependent mechanism mediates mitochondrial Ca(2+) efflux, the molecular identity of this transporter has remained elusive. Here we show that the Na(+)/Ca(2+) exchanger NCLX is enriched in mitochondria, where it is localized to the cristae. Employing Ca(2+) and Na(+) fluorescent imaging, we demonstrate that mitochondrial Na(+)-dependent Ca(2+) efflux is enhanced upon overexpression of NCLX, is reduced by silencing of NCLX expression by siRNA, and is fully rescued by the concomitant expression of heterologous NCLX. NCLX-mediated mitochondrial Ca(2+) transport was inhibited, moreover, by CGP-37157 and exhibited Li(+) dependence, both hallmarks of mitochondrial Na(+)-dependent Ca(2+) efflux. Finally, NCLX-mediated mitochondrial Ca(2+) exchange is blocked in cells expressing a catalytically inactive NCLX mutant. Taken together, our results converge to the conclusion that NCLX is the long-sought mitochondrial Na(+)/Ca(2+) exchanger.

https://www.pnas.org/content/pnas/107/1/436.full.pdf

NCLX is an essential component of mitochondrial Na+/Ca2+ exchange.

Amplification and kinetics of the activation steps in phototransduction

Intact outer segments isolated from bovine retinas (bovine ROS) display a high activity of Na+-Ca2+ exchange, and Na+-Ca2+ exchange appears to be the only functional ion transporter present. Here we demonstrate for the first time that Na+-Ca2+ exchange requires and transports K+ from the following observations. 1) Na+-Ca2+ exchange in bovine ROS required the simultaneous presence of K+ and Ca2+ on one side of the membrane and the presence of Na+ on the other side. 2) Na+-stimulated Ca2+ release from bovine ROS was accompanied by an equally large release of K+. We used the electrogenic protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) as an added electrical shunt; in the intact rod cell, electrogenic Na+-Ca2+ exchange is shunted by K+ channels present in the rod inner segment. In the presence of FCCP, an inward Na+-Ca2+ exchange current was accompanied by an outward current of protons with a stoichiometry of 1 H+/Ca2+; in the absence of FCCP, no Na+-induced proton current was observed. Addition of FCCP did not uncouple Na+-induced K+ release from Na+-induced Ca2+ release. We conclude that Na+-Ca2+ exchange in bovine rod photoreceptors operates at an electrogenic stoichiometry of 4 Na+:(1 Ca2+ + 1 K+). In isolated ROS and in the absence of an external electrical shunt, Na+-Ca2+ exchange operated at an electroneutral stoichiometry of 3 Na+:(1 Ca2+ + 1 K+).

Na+-Ca2+ exchange in bovine rod outer segments requires and transports K+.

http://www.jbc.org/content/early/2007/12/28/jbc.M707521200.full.pdf

SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis

Light causes a rapid lowering of cytosolic free calcium in the outer segments of both retinal rod and cone photoreceptors. This light-induced lowering of calcium is caused by extrusion via a Na–Ca exchanger located in the rod and cone outer segment plasma membrane and plays a key role in the process of light adaptation. The Na–Ca exchanger in retinal rod outer segment was shown earlier to be a novel Na–Ca+K exchanger (NCKX), and its cDNA was obtained by molecular cloning from several mammalian species. On the other hand, the proper identity of the retinal cone Na–Ca exchanger, in terms of both functional characteristics (e.g., requirement for and transport of potassium) and molecular identity, has not yet been elucidated. Here, we report the molecular cloning, intraretinal localization by in situ hybridization, and initial functional characterization of the chicken and human cone-specific Na–Ca exchangers. In addition we report the chicken rod-specific NCKX. We identified NCKX transcripts in both human and chicken cones and observed strong potassium-dependent Na–Ca exchange activity after heterologous expression of human and chicken cone NCKX cDNAs in cultured insect cells. In situ hybridization in chicken retina showed abundant rod NCKX transcripts only in rod photoreceptors, whereas abundant cone NCKX transcripts were found in most, if not all, cone photoreceptors and also in a subpopulation of retinal ganglion cells. A detailed comparison with the previously described retinal rod and brain NCKX cDNAs is presented.

https://www.jneurosci.org/content/jneuro/20/4/1424.full.pdf

Molecular cloning and functional expression of the potassium-dependent sodium-calcium exchanger from human and chicken retinal cone photoreceptors.

Regulation of free cytosolic Ca2+ concentration in the outer segments of bovine retinal rods by Na-Ca-K exchange measured with fluo-3. I. Efficiency of transport and interactions between cations.

Robert T. Szerencsei

Papers

Na+-Ca2+ exchange in bovine rod outer segments requires and transports K+.

SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis

Molecular cloning and functional expression of the potassium-dependent sodium-calcium exchanger from human and chicken retinal cone photoreceptors.

Regulation of free cytosolic Ca2+ concentration in the outer segments of bovine retinal rods by Na-Ca-K exchange measured with fluo-3. I. Efficiency of transport and interactions between cations.

Intracellular Ca2+ sequestration and release in intact bovine retinal rod outer segments. Role in inactivation of Na-Ca+K exchange.