ID NCLX_HUMAN Reviewed; 584 AA. AC Q6J4K2; A6NP50; Q4KMS9; Q6J4K1; Q9H6I8; DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot. DT 10-JAN-2006, sequence version 2. DT 27-MAR-2024, entry version 152. DE RecName: Full=Mitochondrial sodium/calcium exchanger protein {ECO:0000305}; DE AltName: Full=Na(+)/K(+)/Ca(2+)-exchange protein 6 {ECO:0000250|UniProtKB:Q925Q3}; DE AltName: Full=Sodium/calcium exchanger protein, mitochondrial {ECO:0000303|PubMed:15060069}; DE AltName: Full=Sodium/potassium/calcium exchanger 6 {ECO:0000250|UniProtKB:Q925Q3}; DE AltName: Full=Solute carrier family 24 member 6 {ECO:0000312|HGNC:HGNC:26175}; DE AltName: Full=Solute carrier family 8 member B1 {ECO:0000312|HGNC:HGNC:26175}; DE Flags: Precursor; GN Name=SLC8B1 {ECO:0000312|HGNC:HGNC:26175}; GN Synonyms=NCKX6 {ECO:0000250|UniProtKB:Q925Q3}, NCLX GN {ECO:0000303|PubMed:15060069}, SLC24A6 {ECO:0000312|HGNC:HGNC:26175}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, TRANSPORTER RP ACTIVITY (ISOFORMS 1 AND 2), AND ACTIVITY REGULATION. RX PubMed=15060069; DOI=10.1074/jbc.m401229200; RA Palty R., Ohana E., Hershfinkel M., Volokita M., Elgazar V., Beharier O., RA Silverman W.F., Argaman M., Sekler I.; RT "Lithium-calcium exchange is mediated by a distinct potassium-independent RT sodium-calcium exchanger."; RL J. Biol. Chem. 279:25234-25240(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 185-584 (ISOFORM 1). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=20018762; DOI=10.1073/pnas.0908099107; RA Palty R., Silverman W.F., Hershfinkel M., Caporale T., Sensi S.L., RA Parnis J., Nolte C., Fishman D., Shoshan-Barmatz V., Herrmann S., RA Khananshvili D., Sekler I.; RT "NCLX is an essential component of mitochondrial Na+/Ca2+ exchange."; RL Proc. Natl. Acad. Sci. U.S.A. 107:436-441(2010). RN [7] RP FUNCTION. RX PubMed=22829870; DOI=10.1371/journal.pone.0039722; RA Tarasov A.I., Semplici F., Ravier M.A., Bellomo E.A., Pullen T.J., RA Gilon P., Sekler I., Rizzuto R., Rutter G.A.; RT "The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP RT increases in pancreatic beta-cells."; RL PLoS ONE 7:E39722-E39722(2012). RN [8] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=23056385; DOI=10.1371/journal.pone.0046649; RA Nita I.I., Hershfinkel M., Fishman D., Ozeri E., Rutter G.A., Sensi S.L., RA Khananshvili D., Lewis E.C., Sekler I.; RT "The mitochondrial na(+)/ca(2+) exchanger upregulates glucose dependent RT ca(2+) signalling linked to insulin secretion."; RL PLoS ONE 7:E46649-E46649(2012). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, AND ACTIVITY REGULATION. RX PubMed=24898248; DOI=10.1074/jbc.m113.540898; RA De Marchi U., Santo-Domingo J., Castelbou C., Sekler I., Wiederkehr A., RA Demaurex N.; RT "NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, RT thereby limiting Ca2+-induced NAD(P)H production and modulating matrix RT redox state."; RL J. Biol. Chem. 289:20377-20385(2014). RN [10] RP PHOSPHORYLATION AT SER-258, AND MUTAGENESIS OF SER-258. RX PubMed=26440884; DOI=10.1016/j.celrep.2015.08.079; RA Kostic M., Ludtmann M.H., Bading H., Hershfinkel M., Steer E., Chu C.T., RA Abramov A.Y., Sekler I.; RT "PKA phosphorylation of NCLX reverses mitochondrial calcium overload and RT depolarization, promoting survival of PINK1-deficient dopaminergic RT neurons."; RL Cell Rep. 13:376-386(2015). RN [11] RP FUNCTION, TRANSPORTER ACTIVITY (ISOFORM 1), AND MUTAGENESIS OF ASN-149; RP PRO-152; ASP-153; GLY-176; ASN-467; SER-468; ASP-471; GLY-494 AND ASN-498. RX PubMed=28130126; DOI=10.1016/j.bbamcr.2017.01.011; RA Roy S., Dey K., Hershfinkel M., Ohana E., Sekler I.; RT "Identification of residues that control Li+ versus Na+ dependent Ca2+ RT exchange at the transport site of the mitochondrial NCLX."; RL Biochim. Biophys. Acta 1864:997-1008(2017). RN [12] RP FUNCTION. RX PubMed=28219928; DOI=10.15252/embj.201592481; RA Ben-Kasus Nissim T., Zhang X., Elazar A., Roy S., Stolwijk J.A., Zhou Y., RA Motiani R.K., Gueguinou M., Hempel N., Hershfinkel M., Gill D.L., RA Trebak M., Sekler I.; RT "Mitochondria control store-operated Ca(2+) entry through Na(+) and redox RT signals."; RL EMBO J. 36:797-815(2017). CC -!- FUNCTION: Mitochondrial sodium/calcium antiporter that mediates sodium- CC dependent calcium efflux from mitochondrion, by mediating the exchange CC of 3 sodium ions per 1 calcium ion (PubMed:15060069, PubMed:20018762, CC PubMed:22829870, PubMed:23056385, PubMed:24898248, PubMed:28219928, CC PubMed:28130126). Plays a central role in mitochondrial calcium CC homeostasis by mediating mitochondrial calcium extrusion: calcium CC efflux is essential for mitochondrial function and cell survival, CC notably in cardiomyocytes (By similarity). Regulates rates of glucose- CC dependent insulin secretion in pancreatic beta-cells during the first CC phase of insulin secretion: acts by mediating efflux of calcium from CC mitochondrion, thereby affecting cytoplasmic calcium responses CC (PubMed:23056385). Required for store-operated Ca(2+) entry (SOCE) and CC Ca(2+) release-activated Ca(2+) (CRAC) channel regulation: sodium CC transport by SLC8B1 leads to promote calcium-shuttling that modulates CC mitochondrial redox status, thereby regulating SOCE activity CC (PubMed:28219928). Involved in B-lymphocyte chemotaxis (By similarity). CC Able to transport Ca(2+) in exchange of either Li(+) or Na(+), CC explaining how Li(+) catalyzes Ca(2+) exchange (PubMed:15060069, CC PubMed:28130126). In contrast to other members of the family its CC function is independent of K(+) (PubMed:15060069). CC {ECO:0000250|UniProtKB:Q925Q3, ECO:0000269|PubMed:15060069, CC ECO:0000269|PubMed:20018762, ECO:0000269|PubMed:22829870, CC ECO:0000269|PubMed:23056385, ECO:0000269|PubMed:24898248, CC ECO:0000269|PubMed:28219928}. CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=Ca(2+)(in) + 3 Na(+)(out) = Ca(2+)(out) + 3 Na(+)(in); CC Xref=Rhea:RHEA:69955, ChEBI:CHEBI:29101, ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:15060069, ECO:0000269|PubMed:28130126, CC ECO:0000305|PubMed:23056385, ECO:0000305|PubMed:24898248}; CC -!- CATALYTIC ACTIVITY: [Isoform 2]: CC Reaction=Ca(2+)(in) + 3 Na(+)(out) = Ca(2+)(out) + 3 Na(+)(in); CC Xref=Rhea:RHEA:69955, ChEBI:CHEBI:29101, ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:15060069}; CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=Ca(2+)(in) + 3 Li(+)(out) = Ca(2+)(out) + 3 Li(+)(in); CC Xref=Rhea:RHEA:72631, ChEBI:CHEBI:29108, ChEBI:CHEBI:49713; CC Evidence={ECO:0000269|PubMed:15060069, ECO:0000269|PubMed:28130126}; CC -!- CATALYTIC ACTIVITY: [Isoform 2]: CC Reaction=Ca(2+)(in) + 3 Li(+)(out) = Ca(2+)(out) + 3 Li(+)(in); CC Xref=Rhea:RHEA:72631, ChEBI:CHEBI:29108, ChEBI:CHEBI:49713; CC Evidence={ECO:0000269|PubMed:15060069}; CC -!- ACTIVITY REGULATION: Inhibited by the sodium/calcium exchanger CC inhibitor CGP-37157 (PubMed:24898248). Strongly inhibited by zinc CC (PubMed:15060069). {ECO:0000269|PubMed:15060069, CC ECO:0000269|PubMed:24898248}. CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane CC {ECO:0000269|PubMed:20018762, ECO:0000269|PubMed:23056385}; Multi-pass CC membrane protein {ECO:0000269|PubMed:20018762, CC ECO:0000269|PubMed:23056385}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q6J4K2-1; Sequence=Displayed; CC Name=2; Synonyms=S-NCLX {ECO:0000303|PubMed:15060069}; CC IsoId=Q6J4K2-2; Sequence=VSP_016996; CC -!- TISSUE SPECIFICITY: Present in pancreatic beta-cells (at protein CC level). {ECO:0000269|PubMed:23056385}. CC -!- PTM: Phosphorylation at Ser-258 by PKA prevents calcium overload. CC {ECO:0000269|PubMed:26440884}. CC -!- SIMILARITY: Belongs to the Ca(2+):cation antiporter (CaCA) (TC 2.A.19) CC family. SLC24A subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAB15271.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY601759; AAT35807.1; -; mRNA. DR EMBL; AY601760; AAT35808.1; -; mRNA. DR EMBL; AC010178; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471054; EAW98050.1; -; Genomic_DNA. DR EMBL; BC098360; AAH98360.1; -; mRNA. DR EMBL; AK025886; BAB15271.1; ALT_INIT; mRNA. DR CCDS; CCDS31909.1; -. [Q6J4K2-1] DR CCDS; CCDS81744.1; -. [Q6J4K2-2] DR RefSeq; NP_001317395.1; NM_001330466.1. [Q6J4K2-2] DR RefSeq; NP_079235.2; NM_024959.3. [Q6J4K2-1] DR RefSeq; XP_006719670.1; XM_006719607.2. DR RefSeq; XP_011537051.1; XM_011538749.2. DR RefSeq; XP_011537054.1; XM_011538752.2. DR AlphaFoldDB; Q6J4K2; -. DR BioGRID; 123078; 4. DR IntAct; Q6J4K2; 1. DR STRING; 9606.ENSP00000447091; -. DR BindingDB; Q6J4K2; -. DR ChEMBL; CHEMBL3763001; -. DR GuidetoPHARMACOLOGY; 1050; -. DR TCDB; 2.A.19.4.4; the ca(2+):cation antiporter (caca) family. DR GlyCosmos; Q6J4K2; 1 site, No reported glycans. DR GlyGen; Q6J4K2; 1 site. DR iPTMnet; Q6J4K2; -. DR PhosphoSitePlus; Q6J4K2; -. DR SwissPalm; Q6J4K2; -. DR BioMuta; SLC8B1; -. DR DMDM; 85681048; -. DR jPOST; Q6J4K2; -. DR MassIVE; Q6J4K2; -. DR MaxQB; Q6J4K2; -. DR PaxDb; 9606-ENSP00000447091; -. DR PeptideAtlas; Q6J4K2; -. DR ProteomicsDB; 66508; -. [Q6J4K2-1] DR ProteomicsDB; 66509; -. [Q6J4K2-2] DR Antibodypedia; 31257; 116 antibodies from 26 providers. DR DNASU; 80024; -. DR Ensembl; ENST00000202831.7; ENSP00000202831.3; ENSG00000089060.12. [Q6J4K2-1] DR Ensembl; ENST00000546737.5; ENSP00000450081.1; ENSG00000089060.12. [Q6J4K2-2] DR Ensembl; ENST00000552014.5; ENSP00000447091.1; ENSG00000089060.12. [Q6J4K2-1] DR Ensembl; ENST00000680972.1; ENSP00000506377.1; ENSG00000089060.12. [Q6J4K2-1] DR GeneID; 80024; -. DR KEGG; hsa:80024; -. DR MANE-Select; ENST00000680972.1; ENSP00000506377.1; NM_001358345.2; NP_001345274.1. DR UCSC; uc001tvc.4; human. [Q6J4K2-1] DR AGR; HGNC:26175; -. DR CTD; 80024; -. DR DisGeNET; 80024; -. DR GeneCards; SLC8B1; -. DR HGNC; HGNC:26175; SLC8B1. DR HPA; ENSG00000089060; Tissue enhanced (adrenal). DR MIM; 609841; gene. DR neXtProt; NX_Q6J4K2; -. DR OpenTargets; ENSG00000089060; -. DR PharmGKB; PA134954965; -. DR VEuPathDB; HostDB:ENSG00000089060; -. DR eggNOG; KOG2399; Eukaryota. DR GeneTree; ENSGT00940000157433; -. DR HOGENOM; CLU_004979_3_2_1; -. DR InParanoid; Q6J4K2; -. DR OMA; IWIMNIA; -. DR OrthoDB; 5482417at2759; -. DR PhylomeDB; Q6J4K2; -. DR TreeFam; TF323444; -. DR PathwayCommons; Q6J4K2; -. DR Reactome; R-HSA-425561; Sodium/Calcium exchangers. DR Reactome; R-HSA-8949215; Mitochondrial calcium ion transport. DR SignaLink; Q6J4K2; -. DR BioGRID-ORCS; 80024; 14 hits in 1142 CRISPR screens. DR ChiTaRS; SLC8B1; human. DR GenomeRNAi; 80024; -. DR Pharos; Q6J4K2; Tbio. DR PRO; PR:Q6J4K2; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q6J4K2; Protein. DR Bgee; ENSG00000089060; Expressed in left adrenal gland cortex and 155 other cell types or tissues. DR ExpressionAtlas; Q6J4K2; baseline and differential. DR GO; GO:0016020; C:membrane; IBA:GO_Central. DR GO; GO:0030061; C:mitochondrial crista; IDA:BHF-UCL. DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome. DR GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl. DR GO; GO:0015368; F:calcium:monoatomic cation antiporter activity; TAS:Reactome. DR GO; GO:0005432; F:calcium:sodium antiporter activity; IDA:UniProtKB. DR GO; GO:0086038; F:calcium:sodium antiporter activity involved in regulation of cardiac muscle cell membrane potential; ISS:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IPI:BHF-UCL. DR GO; GO:0099093; P:calcium export from the mitochondrion; IDA:UniProtKB. DR GO; GO:0042593; P:glucose homeostasis; IDA:UniProtKB. DR GO; GO:0006874; P:intracellular calcium ion homeostasis; IBA:GO_Central. DR GO; GO:0051560; P:mitochondrial calcium ion homeostasis; IDA:UniProtKB. DR GO; GO:0006851; P:mitochondrial calcium ion transmembrane transport; IDA:UniProtKB. DR GO; GO:0006811; P:monoatomic ion transport; TAS:Reactome. DR GO; GO:0086036; P:regulation of cardiac muscle cell membrane potential; TAS:BHF-UCL. DR GO; GO:0051480; P:regulation of cytosolic calcium ion concentration; IMP:BHF-UCL. DR GO; GO:0050796; P:regulation of insulin secretion; IDA:UniProtKB. DR GO; GO:1901623; P:regulation of lymphocyte chemotaxis; ISS:UniProtKB. DR GO; GO:2001256; P:regulation of store-operated calcium entry; IDA:UniProtKB. DR GO; GO:0050896; P:response to stimulus; IEA:UniProtKB-KW. DR Gene3D; 1.20.1420.30; NCX, central ion-binding region; 2. DR InterPro; IPR004837; NaCa_Exmemb. DR InterPro; IPR044880; NCX_ion-bd_dom_sf. DR PANTHER; PTHR12266:SF0; MITOCHONDRIAL SODIUM_CALCIUM EXCHANGER PROTEIN; 1. DR PANTHER; PTHR12266; NA+/CA2+ K+ INDEPENDENT EXCHANGER; 1. DR Pfam; PF01699; Na_Ca_ex; 2. DR Genevisible; Q6J4K2; HS. PE 1: Evidence at protein level; KW Alternative splicing; Antiport; Calcium; Calcium transport; Glycoprotein; KW Ion transport; Lithium; Membrane; Mitochondrion; KW Mitochondrion inner membrane; Phosphoprotein; Reference proteome; KW Sensory transduction; Sodium; Sodium transport; Transit peptide; KW Transmembrane; Transmembrane helix; Transport. FT TRANSIT 1..26 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 27..584 FT /note="Mitochondrial sodium/calcium exchanger protein" FT /id="PRO_0000045756" FT TOPO_DOM 27..95 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 96..116 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 117..140 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 141..161 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 162..168 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 169..189 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 190..200 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 201..221 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 222..226 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 227..247 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 248..325 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 326..346 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 347..360 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 361..381 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TOPO_DOM 382..383 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 384..404 FT /note="Helical; Name=8" FT /evidence="ECO:0000255" FT TOPO_DOM 405..416 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 417..437 FT /note="Helical; Name=9" FT /evidence="ECO:0000255" FT TOPO_DOM 438..445 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 446..466 FT /note="Helical; Name=10" FT /evidence="ECO:0000255" FT TOPO_DOM 467..487 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 488..508 FT /note="Helical; Name=11" FT /evidence="ECO:0000255" FT TOPO_DOM 509..524 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 525..545 FT /note="Helical; Name=12" FT /evidence="ECO:0000255" FT TOPO_DOM 546..558 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 559..579 FT /note="Helical; Name=13" FT /evidence="ECO:0000255" FT TOPO_DOM 580..584 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT MOD_RES 258 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:26440884" FT CARBOHYD 60 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 176..231 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15060069" FT /id="VSP_016996" FT VARIANT 222 FT /note="R -> C (in dbSNP:rs16942745)" FT /id="VAR_050224" FT VARIANT 358 FT /note="L -> F (in dbSNP:rs3764034)" FT /id="VAR_050225" FT MUTAGEN 149 FT /note="N->A: Lithium-selective; displays reduced FT calcium:sodium antiporter activity while retaining almost FT normal calcium:lithium antiporter activity." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 152 FT /note="P->A: Lithium-selective; displays markedly reduced FT calcium:sodium antiporter activity while retaining almost FT normal calcium:lithium antiporter activity." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 153 FT /note="D->A: Lithium-selective; displays markedly reduced FT calcium:sodium antiporter activity while retaining almost FT normal calcium:lithium antiporter activity." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 176 FT /note="G->A: Non-selective; displays similar reduction of FT calcium:sodium and calcium:lithium antiporter activities." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 258 FT /note="S->A: Abolished ability to prevent calcium FT overload." FT /evidence="ECO:0000269|PubMed:26440884" FT MUTAGEN 258 FT /note="S->D: Phosphomimetic mutant; prevents calcium FT overload." FT /evidence="ECO:0000269|PubMed:26440884" FT MUTAGEN 467 FT /note="N->A: Has no effect on calcium:sodium antiporter FT activity." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 467 FT /note="N->Q: Lithium-selective; displays markedly reduced FT calcium:sodium antiporter activity while retaining normal FT calcium:lithium antiporter activity." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 468 FT /note="S->T: Lithium-selective; displays markedly reduced FT calcium:sodium antiporter activity while retaining almost FT normal calcium:lithium antiporter activity." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 471 FT /note="D->A: Sodium-selective; has little effect on FT calcium:sodium antiporter activity while displaying FT markedly reduced calcium:lithium antiporter activity." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 471 FT /note="D->E: Non-selective; displays reduction of both FT calcium:sodium and calcium:lithium antiporter activities." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 494 FT /note="G->S: Lithium-selective; displays markedly reduced FT calcium:sodium antiporter activity while retaining almost FT normal calcium:lithium antiporter activity." FT /evidence="ECO:0000269|PubMed:28130126" FT MUTAGEN 498 FT /note="N->A: Non-selective; displays similar reduction of FT calcium:sodium and calcium:lithium antiporter activities." FT /evidence="ECO:0000269|PubMed:28130126" FT CONFLICT 57 FT /note="C -> R (in Ref. 1; AAT35807)" FT /evidence="ECO:0000305" FT CONFLICT 130 FT /note="S -> P (in Ref. 1; AAT35807)" FT /evidence="ECO:0000305" FT CONFLICT 281 FT /note="N -> S (in Ref. 1; AAT35807)" FT /evidence="ECO:0000305" SQ SEQUENCE 584 AA; 64231 MW; 6B7008661CC12872 CRC64; MAGRRLNLRW ALSVLCVLLM AETVSGTRGS STGAHISPQF PASGVNQTPV VDCRKVCGLN VSDRCDFIRT NPDCHSDGGY LDYLEGIFCH FPPSLLPLAV TLYVSWLLYL FLILGVTAAK FFCPNLSAIS TTLKLSHNVA GVTFLAFGNG APDIFSALVA FSDPHTAGLA LGALFGAGVL VTTVVAGGIT ILHPFMAASR PFFRDIVFYM VAVFLTFLML FRGRVTLAWA LGYLGLYVFY VVTVILCTWI YQRQRRGSLF CPMPVTPEIL SDSEEDRVSS NTNSYDYGDE YRPLFFYQET TAQILVRALN PLDYMKWRRK SAYWKALKVF KLPVEFLLLL TVPVVDPDKD DQNWKRPLNC LHLVISPLVV VLTLQSGTYG VYEIGGLVPV WVVVVIAGTA LASVTFFATS DSQPPRLHWL FAFLGFLTSA LWINAAATEV VNILRSLGVV FRLSNTVLGL TLLAWGNSIG DAFSDFTLAR QGYPRMAFSA CFGGIIFNIL VGVGLGCLLQ ISRSHTEVKL EPDGLLVWVL AGALGLSLVF SLVSVPLQCF QLSRVYGFCL LLFYLNFLVV ALLTEFGVIH LKSM //