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Gene Review

SLC8A1  -  solute carrier family 8 (sodium/calcium...

Homo sapiens

Synonyms: CNC, NCX1, Na(+)/Ca(2+)-exchange protein 1, Sodium/calcium exchanger 1, Solute carrier family 8 member 1
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Disease relevance of SLC8A1

  • Therefore, we examined whether genetic variations in NCX1 were associated with hypertension [1].
  • We speculate that by using Na+ exchange, NCX-1 couples H+ extrusion with Ca2+ fluxes during bone resorption [2].
  • These results suggest that NCX1 might play an important role in transient focal cerebral ischemia [3].
  • In the heart, NCX1 predominantly operates in forward mode to extrude Ca(2+); however, reverse-mode NCX1 activity during ischemia/reperfusion (IR) contributes to Ca(2+) loading and electrical and contractile dysfunction [4].
  • We report here that mutation of the cardiac-specific NCX1 (NCX1h) gene causes embryonic lethal cardiac arrhythmia in zebrafish tremblor (tre) embryos [5].

Psychiatry related information on SLC8A1


High impact information on SLC8A1

  • Specifically, new (derived) alleles of SNPs within CNCs are rarer than new alleles in nonconserved regions (P = 3 x 10(-18)), indicating that evolutionary pressure has suppressed CNC-derived allele frequencies [7].
  • These findings indicate that salt-sensitive hypertension is triggered by Ca(2+) entry through NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically [8].
  • We further show that acyl CoAs may interact directly with the XIP (exchanger inhibitory peptide) sequence, a known region of anionic lipid modulation, to dynamically regulate NCX1 activity and Ca(2+) homeostasis [4].
  • We applied a combination of ultrastructural and functional imaging methods to assess the subcellular distribution and role of NCX1 in rat CA1 pyramidal cells [9].
  • Quantitative electron microscopic analysis of preembedding immunogold reactions revealed uniform densities of NCX1 along the shafts of apical and basal dendrites, but densities in dendritic shafts were approximately seven times higher than in dendritic spines [9].

Chemical compound and disease context of SLC8A1


Biological context of SLC8A1

  • The stoichiometry with which the Na+/Ca2+ exchanger, NCX1, binds and transports Na+ and Ca2+ has dramatic consequences for ionic homeostasis and cellular function of heart mycocytes and brain neurons, where the exchanger is highly expressed [13].
  • This system provides the advantages of a high level of NCX1 protein expression, very low background ion transport levels, and excellent control over clamped voltage and ionic composition [13].
  • Both NCX1 and NCX2 feature an unusual 1.8-kb exon, containing two-thirds of the protein coding sequence and a similar area of the coding sequences split into several small exons, displaying tissue-specific alternative splicing [14].
  • As part of an effort to determine whether the exchanger is associated with any genetic disorders of the heart or blood pressure, we have assigned the exchanger gene (designated NCX1) to human chromosome 2p21-p23 by analysis of a panel of mouse-human somatic cell hybrids and by in situ hybridization [15].
  • The NCX1 gene consists of 12 exons spread over 200 kb on chromosome 2 close to STS D2S2328 and encodes a 6.2-kb transcript [14].

Anatomical context of SLC8A1


Associations of SLC8A1 with chemical compounds

  • Glutathione S-transferase pull-down experiments revealed that NCX1 interacts with the cytosolic C terminus of TRPC3 [20].
  • NCX1 immunoreactivity was detectable in HEK293 as well as in TRPC3-overexpressing HEK293 cells, and reduction of extracellular Na(+) after Na(+) loading with monensin resulted in significant rises in intracellular free Ca(2+) (Ca(2+)(i)) of HEK293 cells [20].
  • Subepi- and subendocardial sections were analyzed by Northern blot for steady-state mRNA levels of SERCA2a, Na(+)-Ca2+ exchanger (NCX1), ANP, and BNP [21].
  • Here we identify the role of Na(+)/Ca(2+) exchanger type 1 (NCX1) in salt-sensitive hypertension using SEA0400, a specific inhibitor of Ca(2+) entry through NCX1, and genetically engineered mice [8].
  • Several abundant PM proteins co-immunoprecipitated with NCX1, including the alpha2 and alpha3 isoforms of the Na(+) pump catalytic (alpha) subunit, and the alpha2 subunit of the dihydropyridine receptor [18].

Physical interactions of SLC8A1


Other interactions of SLC8A1

  • The 14-3-3epsilon protein also inhibited the NCX1 and NCX3 isoforms [23].
  • PLN protein levels were reduced by 23 +/- 6% (P < 0.05) in endo compared to epi in the failing heart and by 17 +/- 25% (non-significant) in the nonfailing heart, whereas CS protein levels and NCX1 mRNA levels were similar across the left ventricular wall [21].
  • Co-immunoprecipitation experiments with PLM and split exchangers suggest that PLM associated with the N-terminal domain of NCX1 when it contained intracellular loop residues 218-358 [24].
  • We observed significant (P < 0.05) induction in transcript level of ATP-driven ion exchangers (Atp1A1, NCX-1, SERCA2a), ion channels (L-type Ca(2+)-channel, K(ir)3.4, Na(v)1.5) and RyR-2 in hypertrophic hearts, while gene expression was repressed in diseased human hearts [25].

Analytical, diagnostic and therapeutic context of SLC8A1


  1. Association of genetic polymorphisms of sodium-calcium exchanger 1 gene, NCX1, with hypertension in a Japanese general population. Kokubo, Y., Inamoto, N., Tomoike, H., Kamide, K., Takiuchi, S., Kawano, Y., Tanaka, C., Katanosaka, Y., Wakabayashi, S., Shigekawa, M., Hishikawa, O., Miyata, T. Hypertens. Res. (2004) [Pubmed]
  2. Identification and characterization of a sodium/calcium exchanger, NCX-1, in osteoclasts and its role in bone resorption. Moonga, B.S., Davidson, R., Sun, L., Adebanjo, O.A., Moser, J., Abedin, M., Zaidi, N., Huang, C.L., Zaidi, M. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  3. Selective alteration of expression of Na+/Ca2+ exchanger isoforms after transient focal cerebral ischemia in rats. Li, L.L., Sun, L.N., Zhou, H.Y., Li, Z.B., Wang, X.L. Neurosci. Lett. (2006) [Pubmed]
  4. Metabolic regulation of sodium-calcium exchange by intracellular acyl CoAs. Riedel, M.J., Baczk??, I., Searle, G.J., Webster, N., Fercho, M., Jones, L., Lang, J., Lytton, J., Dyck, J.R., Light, P.E. EMBO J. (2006) [Pubmed]
  5. Calcium extrusion is critical for cardiac morphogenesis and rhythm in embryonic zebrafish hearts. Ebert, A.M., Hume, G.L., Warren, K.S., Cook, N.P., Burns, C.G., Mohideen, M.A., Siegal, G., Yelon, D., Fishman, M.C., Garrity, D.M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. HiResolution and conventional sound processing in the HiResolution bionic ear: using appropriate outcome measures to assess speech recognition ability. Koch, D.B., Osberger, M.J., Segel, P., Kessler, D. Audiol. Neurootol. (2004) [Pubmed]
  7. Conserved noncoding sequences are selectively constrained and not mutation cold spots. Drake, J.A., Bird, C., Nemesh, J., Thomas, D.J., Newton-Cheh, C., Reymond, A., Excoffier, L., Attar, H., Antonarakis, S.E., Dermitzakis, E.T., Hirschhorn, J.N. Nat. Genet. (2006) [Pubmed]
  8. Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle. Iwamoto, T., Kita, S., Zhang, J., Blaustein, M.P., Arai, Y., Yoshida, S., Wakimoto, K., Komuro, I., Katsuragi, T. Nat. Med. (2004) [Pubmed]
  9. Differential distribution of NCX1 contributes to spine-dendrite compartmentalization in CA1 pyramidal cells. Lörincz, A., Rózsa, B., Katona, G., Vizi, E.S., Tamás, G. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  10. Involvement of Na+-Ca2+ exchanger in intracellular Ca2+ increase and neuronal injury induced by polychlorinated biphenyls in human neuroblastoma SH-SY5Y cells. Magi, S., Castaldo, P., Carrieri, G., Scorziello, A., Di Renzo, G., Amoroso, S. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  11. Cyclosporin A regulates sodium-calcium exchanger (NCX1) gene expression in vitro and cardiac hypertrophy in NCX1 transgenic mice. Jordan, M.C., Quednau, B.D., Roos, K.P., Ross, R.S., Philipson, K.D., Nicholas, S.B. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  12. On titanium frameworks and alternative impression techniques in implant dentistry. Ortorp, A. Swedish dental journal. Supplement. (2005) [Pubmed]
  13. Stoichiometry of the Cardiac Na+/Ca2+ exchanger NCX1.1 measured in transfected HEK cells. Dong, H., Dunn, J., Lytton, J. Biophys. J. (2002) [Pubmed]
  14. The organization of the human gene NCX1 encoding the sodium-calcium exchanger. Kraev, A., Chumakov, I., Carafoli, E. Genomics (1996) [Pubmed]
  15. Mapping of the gene for the cardiac sarcolemmal Na(+)-Ca2+ exchanger to human chromosome 2p21-p23. Shieh, B.H., Xia, Y., Sparkes, R.S., Klisak, I., Lusis, A.J., Nicoll, D.A., Philipson, K.D. Genomics (1992) [Pubmed]
  16. Cloning of the multipartite promoter of the sodium-calcium exchanger gene NCX1 and characterization of its activity in vascular smooth muscle cells. Scheller, T., Kraev, A., Skinner, S., Carafoli, E. J. Biol. Chem. (1998) [Pubmed]
  17. NCX1 Na/Ca exchanger splice variants in pancreatic islet cells. Van Eylen, F., Bollen, A., Herchuelz, A. J. Endocrinol. (2001) [Pubmed]
  18. Plasma membrane-cytoskeleton-endoplasmic reticulum complexes in neurons and astrocytes. Lencesova, L., O'Neill, A., Resneck, W.G., Bloch, R.J., Blaustein, M.P. J. Biol. Chem. (2004) [Pubmed]
  19. Phospholipase C-dependent control of cardiac calcium homeostasis involves a TRPC3-NCX1 signaling complex. Eder, P., Probst, D., Rosker, C., Poteser, M., Wolinski, H., Kohlwein, S.D., Romanin, C., Groschner, K. Cardiovasc. Res. (2007) [Pubmed]
  20. Ca(2+) signaling by TRPC3 involves Na(+) entry and local coupling to the Na(+)/Ca(2+) exchanger. Rosker, C., Graziani, A., Lukas, M., Eder, P., Zhu, M.X., Romanin, C., Groschner, K. J. Biol. Chem. (2004) [Pubmed]
  21. Heterogeneous transmural gene expression of calcium-handling proteins and natriuretic peptides in the failing human heart. Prestle, J., Dieterich, S., Preuss, M., Bieligk, U., Hasenfuss, G. Cardiovasc. Res. (1999) [Pubmed]
  22. Evidence for cardiac sodium-calcium exchanger association with caveolin-3. Bossuyt, J., Taylor, B.E., James-Kracke, M., Hale, C.C. FEBS Lett. (2002) [Pubmed]
  23. Inhibitory interaction of the plasma membrane Na+/Ca2+ exchangers with the 14-3-3 proteins. Pulina, M.V., Rizzuto, R., Brini, M., Carafoli, E. J. Biol. Chem. (2006) [Pubmed]
  24. Cytoplasmic tail of phospholemman interacts with the intracellular loop of the cardiac na+/ca2+ exchanger. Wang, J., Zhang, X.Q., Ahlers, B.A., Carl, L.L., Song, J., Rothblum, L.I., Stahl, R.C., Carey, D.J., Cheung, J.Y. J. Biol. Chem. (2006) [Pubmed]
  25. Disease-associated changes in the expression of ion channels, ion receptors, ion exchangers and Ca(2+)-handling proteins in heart hypertrophy. Zwadlo, C., Borlak, J. Toxicol. Appl. Pharmacol. (2005) [Pubmed]
  26. Mapping of the human cardiac Na+/Ca2+ exchanger gene (NCX1) by fluorescent in situ hybridization to chromosome region 2p22-->p23. McDaniel, L.D., Lederer, W.J., Kofuji, P., Schulze, D.H., Kieval, R., Schultz, R.A. Cytogenet. Cell Genet. (1993) [Pubmed]
  27. Spatial organization of the epithelium and the role of neural crest cells in the initiation of the mammalian tooth germ. Lumsden, A.G. Development (1988) [Pubmed]
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