Alternative titles; symbols
HGNC Approved Gene Symbol: SLC8A1
Cytogenetic location: 2p22.1 Genomic coordinates (GRCh38): 2:40,097,270-40,512,435 (from NCBI)
In cardiac myocytes, Ca(2+) concentrations alternate between high levels during contraction and low levels during relaxation. The increase in Ca(2+) concentration during contraction is primarily due to release of Ca(2+) from intracellular stores. However, some Ca(2+) also enters the cell through the sarcolemma (plasma membrane). During relaxation, Ca(2+) is sequestered within the intracellular stores. To prevent overloading of intracellular stores, the Ca(2+) that entered across the sarcolemma must be extruded from the cell. The Na(+)-Ca(2+) exchanger is the primary mechanism by which the Ca(2+) is extruded from the cell during relaxation. In the heart, the exchanger may play a key role in digitalis action. The exchanger is the dominant mechanism in returning the cardiac myocyte to its resting state following excitation (summary by Shieh et al., 1992).
Komuro et al. (1992) cloned human cardiac Na(+)-Ca(2+) exchanger cDNA. They concluded that the cardiac type exchanger mRNA is expressed most abundantly in the heart and next in the brain. It is also expressed in the retina and in skeletal and smooth muscles at very low levels. The levels of mRNA were significantly lower in fetal hearts than in adult hearts but were unchanged in the myocardium from patients with end-stage heart failure.
The cardiac sodium/calcium exchanger (NCX1) is a bidirectional calcium transporter that contributes to the electrical activity of the heart. Kang and Hilgemann (2004) used an ion-selective electrode technique to quantify ion fluxes in giant patches and demonstrated that the ion flux ratios are approximately 3.2 for maximal transport in either direction. With sodium and calcium ions on both sides of the membrane, net current and calcium flux can reverse at different membrane potentials, and inward current can be generated in the absence of cytoplasmic calcium, but not sodium. Kang and Hilgemann (2004) proposed that NCX1 can transport not only 1 calcium or 3 sodium ions, but also 1 calcium with 1 sodium ion at a low rate. Therefore, in addition to the major 3:1 transport mode, import of 1 sodium with 1 calcium defines a sodium-conducting mode that exports 1 calcium ion, and an electroneutral calcium influx mode that exports 3 sodium ions. The 2 minor transport modes can potentially determine resting free calcium and background inward current in the heart.
Two Ca(2+)-binding domains (CBD1 and CBD2), together with the alpha-catenin-like domain, form the regulatory exchanger loop of SLC8A1. By NMR spectroscopy, Hilge et al. (2006) compared the solution structure of CBD1 and CBD2 of canine Slc8a1 and found that they were very similar in the Ca(2+)-bound state, but in the absence of Ca(2+), the upper half of CBD1 unfolded while CBD2 maintained its structural integrity. CBD1 demonstrated a 7-fold higher affinity for Ca(2+) than CBD2. Hilge et al. (2006) concluded that CBD1 is the primary Ca(2+) sensor of SLC8A1.
Kraev et al. (1996) isolated genomic clones of NCX1 and determined that the gene consists of 12 exons spanning 200 kb of DNA. They stated that NCX1 and NCX2 (601901) have similar intron/exon structures, suggesting that they arose by gene duplication.
Shieh et al. (1992) mapped the Na(+)-Ca(2+) exchanger gene, designated NCX1, to chromosome 2 by Southern blot analysis of DNAs from a panel of mouse-human somatic cell hybrids and regionalized the assignment to 2p23-p21 by in situ hybridization. By fluorescence in situ hybridization, McDaniel et al. (1993) narrowed the assignment to 2p23-p22. Kraev et al. (1996) confirmed the earlier mapping of NCX1 on chromosome 2 and stated that the first exon of the gene is located a few nucleotides from STS marker D2S2328.
Nicoll et al. (1996) mapped the mouse Slc8a1 gene to the distal region of chromosome 17.
Wakimoto et al. (2000) generated Ncx1-deficient mice and found that homozygous mice were small and died between embryonic days 9 and 10 without heartbeats or Na(+)-Ca(2+) exchange activity. Cardiac myocytes showed apoptosis. In situ hybridization analysis demonstrated heart-specific expression of Ncx1 at day 9.5 in normal embryos. Histologic analysis of mutant mice revealed thin ventricular walls and sparse cardiac myocytes. Heterozygous adult mice had significantly reduced exchange activity and lower Ncx1 protein content in heart, kidney, aorta, and smooth muscle cells.
Iwamoto et al. (2004) demonstrated that SEA0400, a specific inhibitor of Ca(2+) entry through NCX1, lowered arterial blood pressure in salt-dependent hypertensive rat models, but not in other types of hypertensive rats or in normotensive rats. Infusion of SEA0400 into the femoral artery of salt-dependent hypertensive rats increased arterial blood flow, indicating peripheral vasodilation. SEA0400 reversed ouabain-induced cytosolic Ca(2+) elevation and vasoconstriction in arteries. Heterozygous Ncx1-deficient mice had low salt sensitivity, whereas transgenic mice specifically expressing the Ncx1.3 variant in smooth muscle were hypersensitive to salt. SEA0400 lowered blood pressure in salt-dependent hypertensive mice expressing Ncx1.3, but not in SEA0400-insensitive Ncx1.3 mutants. Iwamoto et al. (2004) concluded that salt-sensitive hypertension is triggered by Ca(2+) entry through NCX1 in arterial smooth muscle.
The hearts of zebrafish tremblor (tre) mutants exhibit chaotic movements and fail to develop synchronized contractions. Langenbacher et al. (2005) found that the tre locus encodes Ncx1. Forced expression of Ncx1 or other calcium-handling molecules restored synchronized heartbeats in tre mutant embryos in a dosage-dependent manner. Ebert et al. (2005) found that the calcium extrusion defects in tre mutants correlated with severe disruption in sarcomere assembly.
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. Calcium extrusion is critical for cardiac morphogenesis and rhythm in embryonic zebrafish hearts. Proc. Nat. Acad. Sci. 102: 17705-17710, 2005. [PubMed: 16314582] [Full Text: https://doi.org/10.1073/pnas.0502683102]
Hilge, M., Aelen, J., Vuister, G. W. Ca(2+) regulation in the Na(+)/Ca(2+) exchanger involves two markedly different Ca(2+) sensors. Molec. Cell 22: 15-25, 2006. [PubMed: 16600866] [Full Text: https://doi.org/10.1016/j.molcel.2006.03.008]
Iwamoto, T., Kita, S., Zhang, J., Blaustein, M. P., Arai, Y., Yoshida, S., Wakimoto, K., Komuro, I., Katsuragi, T. Salt-sensitive hypertension is triggered by Ca(2+) entry via Na+/Ca+ exchanger type-1 in vascular smooth muscle. Nature Med. 10: 1193-1199, 2004. [PubMed: 15475962] [Full Text: https://doi.org/10.1038/nm1118]
Kang, T. M., Hilgemann, D. W. Multiple transport modes of the cardiac Na(+)/CA(2+) exchanger. Nature 427: 544-548, 2004. [PubMed: 14765196] [Full Text: https://doi.org/10.1038/nature02271]
Komuro, I., Wenninger, K. E., Philipson, K. D., Izumo, S. Molecular cloning and characterization of the human cardiac Na(+)/Ca(2+) exchanger cDNA. Proc. Nat. Acad. Sci. 89: 4769-4773, 1992. [PubMed: 1374913] [Full Text: https://doi.org/10.1073/pnas.89.10.4769]
Kraev, A., Chumakov, I., Carafoli, E. The organization of the human gene NCX1 encoding the sodium-calcium exchanger. Genomics 37: 105-112, 1996. [PubMed: 8921376] [Full Text: https://doi.org/10.1006/geno.1996.0526]
Langenbacher, A. D., Dong, Y., Shu, X., Choi, J., Nicoll, D. A., Goldhaber, J. I., Philipson, K. D., Chen, J.-N. Mutation in sodium-calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish. Proc. Nat. Acad. Sci. 102: 17699-17704, 2005. [PubMed: 16314583] [Full Text: https://doi.org/10.1073/pnas.0502679102]
McDaniel, L. D., Lederer, W. J., Kofuji, P., Schulze, D. H., Kieval, R., Schultz, R. A. Mapping of the human cardiac Na+/Ca(2+) exchanger gene (NCX1) by fluorescent in situ hybridization to chromosome region 2p22-p23. Cytogenet. Cell Genet. 63: 192-193, 1993. [PubMed: 8485996] [Full Text: https://doi.org/10.1159/000133532]
Nicoll, D. A., Quednau, B. D., Qui, Z., Xia, Y.-R., Lusis, A. J., Philipson, K. D. Cloning of a third mammalian Na(+)-Ca(2+) exchanger, NCX3. J. Biol. Chem. 271: 24914-24921, 1996. [PubMed: 8798769] [Full Text: https://doi.org/10.1074/jbc.271.40.24914]
Shieh, B.-H., Xia, Y., Sparkes, R. S., Klisak, I., Lusis, A. J., Nicoll, D. A., Philipson, K. D. Mapping of the gene for the cardiac sarcolemmal Na(+)-Ca(2+) exchanger to human chromosome 2p21-p23. Genomics 12: 616-617, 1992. [PubMed: 1559714] [Full Text: https://doi.org/10.1016/0888-7543(92)90459-6]
Wakimoto, K., Kobayashi, K., Kuro-o, M., Yao, A., Iwamoto, T., Yanaka, N., Kita, S., Nishida, A., Azuma, S., Toyoda, Y., Omori, K., Imahie, H., Oka, T., Kudoh, S., Kohmoto, O., Yazaki, Y., Shigekawa, M., Imai, Y., Nabeshima, Y., Komura, I. Targeted disruption of Na(+)/Ca(2+) exchanger gene leads to cardiomyocyte apoptosis and defects in heartbeat. J. Biol. Chem. 275: 36991-36998, 2000. [PubMed: 10967099] [Full Text: https://doi.org/10.1074/jbc.M004035200]