ID SL9A2_MOUSE Reviewed; 814 AA. AC Q3ZAS0; DT 03-MAY-2023, integrated into UniProtKB/Swiss-Prot. DT 27-SEP-2005, sequence version 1. DT 28-JUN-2023, entry version 149. DE RecName: Full=Sodium/hydrogen exchanger 2; DE AltName: Full=Na(+)/H(+) exchanger 2; DE Short=NHE-2; DE AltName: Full=Sodium/hydrogen exchanger; DE AltName: Full=Solute carrier family 9 member 2; GN Name=Slc9a2; Synonyms=Nhe2; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [3] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [4] RP DISRUPTION PHENOTYPE. RX PubMed=9502765; DOI=10.1172/jci1249; RA Schultheis P.J., Clarke L.L., Meneton P., Harline M., Boivin G.P., RA Stemmermann G., Duffy J.J., Doetschman T., Miller M.L., Shull G.E.; RT "Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes RT reduced viability of gastric parietal cells and loss of net acid RT secretion."; RL J. Clin. Invest. 101:1243-1253(1998). RN [5] RP DISRUPTION PHENOTYPE. RX PubMed=11099134; RA Boivin G.P., Schultheis P.J., Shull G.E., Stemmermann G.N.; RT "Variant form of diffuse corporal gastritis in NHE2 knockout mice."; RL Comp. Med. 50:511-515(2000). RN [6] RP DISRUPTION PHENOTYPE. RX PubMed=11705743; DOI=10.1152/ajpgi.2001.281.6.g1385; RA Ledoussal C., Woo A.L., Miller M.L., Shull G.E.; RT "Loss of the NHE2 Na(+)/H(+) exchanger has no apparent effect on diarrheal RT state of NHE3-deficient mice."; RL Am. J. Physiol. 281:G1385-G1396(2001). RN [7] RP FUNCTION, TRANSPORTER ACTIVITY, TISSUE SPECIFICITY, AND ACTIVITY RP REGULATION. RX PubMed=14962844; DOI=10.1152/ajpgi.00332.2003; RA Bachmann O., Riederer B., Rossmann H., Groos S., Schultheis P.J., RA Shull G.E., Gregor M., Manns M.P., Seidler U.; RT "The Na+/H+ exchanger isoform 2 is the predominant NHE isoform in murine RT colonic crypts and its lack causes NHE3 upregulation."; RL Am. J. Physiol. 287:G125-G133(2004). RN [8] RP TISSUE SPECIFICITY, AND FUNCTION. RX PubMed=16690903; DOI=10.1152/ajpgi.00342.2005; RA Guan Y., Dong J., Tackett L., Meyer J.W., Shull G.E., Montrose M.H.; RT "NHE2 is the main apical NHE in mouse colonic crypts but an alternative RT Na+-dependent acid extrusion mechanism is upregulated in NHE2-null mice."; RL Am. J. Physiol. 291:G689-G699(2006). RN [9] RP SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE. RX PubMed=21900251; DOI=10.1074/jbc.m111.268219; RA Xue L., Aihara E., Wang T.C., Montrose M.H.; RT "Trefoil factor 2 requires Na/H exchanger 2 activity to enhance mouse RT gastric epithelial repair."; RL J. Biol. Chem. 286:38375-38382(2011). RN [10] RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY. RX PubMed=34985202; DOI=10.1111/apha.13774; RA Nikolovska K., Cao L., Hensel I., Di Stefano G., Seidler A.E., Zhou K., RA Qian J., Singh A.K., Riederer B., Seidler U.; RT "Sodium/hydrogen-exchanger-2 modulates colonocyte lineage RT differentiation."; RL Acta Physiol. 234:e13774-e13774(2022). CC -!- FUNCTION: Plasma membrane Na(+)/H(+) antiporter (PubMed:14962844, CC PubMed:16690903). Mediates the electroneutral exchange of intracellular CC H(+) ions for extracellular Na(+) (PubMed:14962844). Major apical CC Na(+)/H(+) exchanger in the base of the colonic crypt (PubMed:14962844, CC PubMed:16690903). Controls in the colonic crypt intracellular pH (pHi) CC to direct colonic epithelial cell differentiation into the absorptive CC enterocyte lineage at the expense of the secretory lineage CC (PubMed:34985202, PubMed:14962844). {ECO:0000269|PubMed:14962844, CC ECO:0000269|PubMed:16690903, ECO:0000269|PubMed:34985202}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(out) + Na(+)(in) = H(+)(in) + Na(+)(out); CC Xref=Rhea:RHEA:29419, ChEBI:CHEBI:15378, ChEBI:CHEBI:29101; CC Evidence={ECO:0000269|PubMed:14962844}; CC -!- ACTIVITY REGULATION: In colonic crypts activated by low pHi, CC hyperosmolarity, and an increase in intracellular cAMP levels. CC {ECO:0000269|PubMed:14962844}. CC -!- SUBUNIT: Interacts with CHP1 and CHP2. {ECO:0000250|UniProtKB:P48763}. CC -!- SUBCELLULAR LOCATION: Apical cell membrane CC {ECO:0000269|PubMed:21900251}; Multi-pass membrane protein CC {ECO:0000255}. CC -!- TISSUE SPECIFICITY: Expressed in the colonic epithelium predominantly CC in the cryptal region. Maximally expressed in the luminal membrane near CC the crypt base and in the middle of the crypt (at protein level) CC (PubMed:14962844). Expressed in gastric epithelium (at protein level) CC (PubMed:21900251). {ECO:0000269|PubMed:14962844, CC ECO:0000269|PubMed:21900251}. CC -!- DISRUPTION PHENOTYPE: SLC9A2 null mice do not develop diarrhea, have no CC changes in quantitated intestinal Na(+) absorption, however mice CC develop a sharp reduction in the number of gastric parietal and CC zymogenic cells associated with a loss of net acid secretion in adult CC but not in juvenile mice (PubMed:9502765, PubMed:11099134). SLC9A2 null CC mice also exhibited reduced recovery from laser-induced ulceration of CC the stomach (PubMed:21900251). Double-knockout of SLC9A2 and SLC9A3 are CC not significantly different than the SLC9A3-deficient alone in CC diarrhea, intestinal Na(+) absorption, or reduced life expectancy CC (PubMed:11705743). Steady-state pH intracellular is significantly CC altered along the colonic crypt axis in deficicent mice CC (PubMed:34985202). {ECO:0000269|PubMed:11099134, CC ECO:0000269|PubMed:11705743, ECO:0000269|PubMed:21900251, CC ECO:0000269|PubMed:34985202, ECO:0000269|PubMed:9502765}. CC -!- SIMILARITY: Belongs to the monovalent cation:proton antiporter 1 (CPA1) CC transporter (TC 2.A.36) family. {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; AC154392; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC103685; AAI03686.1; -; mRNA. DR EMBL; BC104737; AAI04738.1; -; mRNA. DR RefSeq; NP_001028461.2; NM_001033289.2. DR SMR; Q3ZAS0; -. DR STRING; 10090.ENSMUSP00000027231; -. DR iPTMnet; Q3ZAS0; -. DR MaxQB; Q3ZAS0; -. DR ProteomicsDB; 336574; -. DR Antibodypedia; 32970; 96 antibodies from 22 providers. DR DNASU; 226999; -. DR Ensembl; ENSMUST00000027231; ENSMUSP00000027231; ENSMUSG00000026062. DR GeneID; 226999; -. DR KEGG; mmu:226999; -. DR UCSC; uc007aun.1; mouse. DR AGR; MGI:105075; -. DR CTD; 6549; -. DR MGI; MGI:105075; Slc9a2. DR VEuPathDB; HostDB:ENSMUSG00000026062; -. DR eggNOG; KOG1966; Eukaryota. DR GeneTree; ENSGT00940000156807; -. DR HOGENOM; CLU_005912_4_3_1; -. DR InParanoid; Q3ZAS0; -. DR OMA; INMFRTI; -. DR OrthoDB; 316731at2759; -. DR TreeFam; TF317212; -. DR Reactome; R-MMU-425986; Sodium/Proton exchangers. DR BioGRID-ORCS; 226999; 2 hits in 72 CRISPR screens. DR Proteomes; UP000000589; Chromosome 1. DR Bgee; ENSMUSG00000026062; Expressed in interventricular septum and 109 other tissues. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0005903; C:brush border; TAS:MGI. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0015386; F:potassium:proton antiporter activity; IBA:GO_Central. DR GO; GO:0015385; F:sodium:proton antiporter activity; IDA:MGI. DR GO; GO:0030855; P:epithelial cell differentiation; IMP:UniProtKB. DR GO; GO:0071805; P:potassium ion transmembrane transport; IBA:GO_Central. DR GO; GO:0008104; P:protein localization; IMP:MGI. DR GO; GO:0051453; P:regulation of intracellular pH; IMP:UniProtKB. DR GO; GO:0006885; P:regulation of pH; IDA:MGI. DR GO; GO:0098719; P:sodium ion import across plasma membrane; IBA:GO_Central. DR GO; GO:0006814; P:sodium ion transport; IDA:MGI. DR Gene3D; 6.10.140.1330; -; 1. DR Gene3D; 6.10.250.1040; -; 1. DR Gene3D; 6.10.250.2020; -; 1. DR InterPro; IPR006153; Cation/H_exchanger. DR InterPro; IPR018422; Cation/H_exchanger_CPA1. DR InterPro; IPR004709; NaH_exchanger. DR InterPro; IPR001953; NHE-2/4. DR InterPro; IPR032103; NHE_CaM-bd. DR PANTHER; PTHR10110; SODIUM/HYDROGEN EXCHANGER; 1. DR PANTHER; PTHR10110:SF89; SODIUM/HYDROGEN EXCHANGER 2; 1. DR Pfam; PF00999; Na_H_Exchanger; 1. DR Pfam; PF16644; NEXCaM_BD; 1. DR PRINTS; PR01084; NAHEXCHNGR. DR PRINTS; PR01086; NAHEXCHNGR2. DR TIGRFAMs; TIGR00840; b_cpa1; 1. PE 1: Evidence at protein level; KW Antiport; Cell membrane; Ion transport; Membrane; Reference proteome; KW Sodium; Sodium transport; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..814 FT /note="Sodium/hydrogen exchanger 2" FT /evidence="ECO:0000255" FT /id="PRO_5015097548" FT TRANSMEM 108..128 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 139..159 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 170..190 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 210..230 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 238..258 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 279..299 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 309..329 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 362..382 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 393..413 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 431..451 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 460..480 FT /note="Helical" FT /evidence="ECO:0000255" FT REGION 647..710 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 740..814 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 677..691 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 692..710 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 752..766 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 772..787 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 799..814 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" SQ SEQUENCE 814 AA; 91646 MW; 8543A204ED2528C2 CRC64; MGPRGTAHSV RAPLSWLLLL LLSLQVAVPA GALAETLLDA PRARGASSNP PSPASVVAPG TTPFEESRLP VFTLDYPHVQ IPFEITLWIL LASLAKIGFH LYHKLPTIVP ESCLLIMVGL LLGGIIFGVD EKSPPAMKTD VFFLYLLPPI VLDAGYFMPT RPFFENFGTI FWYAVVGTLW NSIGIGVSLF GICQIEAFGL SDITLLQNLL FGSLISAVDP VAVLAVFENI HVNEQLYILV FGESLLNDAV TVVLYNLFKS FCQMKTIQTV DVFAGIANFF VVGIGGVLIG ILLGFIAAFT TRFTHNIRVI EPLFVFLYSY LSYITAEMFH LSGIMAITAC AMTMNKYVEE NVSQKSYTTI KYFMKMLSSV SETLIFIFMG VSTVGKNHEW NWAFVCFTLA FCLIWRALGV FVLTQVINWF RTIPLTFKDQ FIIAYGGLRG AICFALVFLL PATVFPRKKL FITAAIVVIF FTVFILGITI RPLVEFLDVK RSNKKQQAVS EEIHCRFFDH VKTGIEDVCG HWGHNFWRDK FKKFDDKYLR KLLIRENQPK SSIVSLYKKL EIKHAIEMAE TGMISTVPSF ASLNDCREEK IRKLTPGEMD EIREILSRNL YQIRQRTLSY NRHNLTADTS ERQAKEILIR RRHSLRESLR KDNSSNRERR ASTSTSRYLS LPKNTKLPEK LQKKKKVSNA DGNSSDSDPD VGTTVLNLQP RTRRFLPDQF SKKASQAYKM EWKNEVDVGS VRVPPSVSPA PRSKDGGTQT PGLLRQPLLS KDQRFGRGRE DSLTEDVPPK PPPRLVRRAS EPGNRKGRLG NEKP //