SL9A3_HUMAN
ID SL9A3_HUMAN Reviewed; 834 AA.
AC P48764; B7ZKR2; E9PF67; Q3MIW3;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 2.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Sodium/hydrogen exchanger 3 {ECO:0000305};
DE AltName: Full=Na(+)/H(+) exchanger 3 {ECO:0000303|PubMed:7631746};
DE Short=NHE-3 {ECO:0000303|PubMed:7631746};
DE AltName: Full=Solute carrier family 9 member 3;
GN Name=SLC9A3 {ECO:0000312|HGNC:HGNC:11073};
GN Synonyms=NHE3 {ECO:0000303|PubMed:7631746};
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] (ISOFORM 1), AND VARIANT ARG-799.
RC TISSUE=Kidney cortex;
RX PubMed=7631746; DOI=10.1152/ajpcell.1995.269.1.c198;
RA Brant S.R., Yun C.H., Donowitz M., Tse C.-M.;
RT "Cloning, tissue distribution, and functional analysis of the human Na+/N+
RT exchanger isoform, NHE3.";
RL Am. J. Physiol. 269:C198-C206(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ARG-799.
RC TISSUE=Colon;
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 [4]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH PDZD3.
RX PubMed=19088451; DOI=10.1159/000185553;
RA Zachos N.C., Hodson C., Kovbasnjuk O., Li X., Thelin W.R., Cha B.,
RA Milgram S., Donowitz M.;
RT "Elevated intracellular calcium stimulates NHE3 activity by an IKEPP
RT (NHERF4) dependent mechanism.";
RL Cell. Physiol. Biochem. 22:693-704(2008).
RN [5]
RP INTERACTION WITH AHCYL1.
RX PubMed=18829453; DOI=10.1074/jbc.m805534200;
RA He P., Zhang H., Yun C.C.;
RT "IRBIT, inositol 1,4,5-triphosphate (IP3) receptor-binding protein released
RT with IP3, binds Na+/H+ exchanger NHE3 and activates NHE3 activity in
RT response to calcium.";
RL J. Biol. Chem. 283:33544-33553(2008).
RN [6]
RP INTERACTION WITH AHCYL1.
RX PubMed=20584908; DOI=10.1074/jbc.m110.133066;
RA He P., Klein J., Yun C.C.;
RT "Activation of Na+/H+ exchanger NHE3 by angiotensin II is mediated by
RT inositol 1,4,5-triphosphate (IP3) receptor-binding protein released with
RT IP3 (IRBIT) and Ca2+/calmodulin-dependent protein kinase II.";
RL J. Biol. Chem. 285:27869-27878(2010).
RN [7]
RP VARIANTS DIAR8 THR-127; THR-269; VAL-311 AND GLN-382, CHARACTERIZATION OF
RP VARIANTS DIAR8 THR-127; THR-269; VAL-311 AND GLN-382, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=26358773; DOI=10.1093/hmg/ddv367;
RA Janecke A.R., Heinz-Erian P., Yin J., Petersen B.S., Franke A., Lechner S.,
RA Fuchs I., Melancon S., Uhlig H.H., Travis S., Marinier E., Perisic V.,
RA Ristic N., Gerner P., Booth I.W., Wedenoja S., Baumgartner N.,
RA Vodopiutz J., Frechette-Duval M.C., De Lafollie J., Persad R., Warner N.,
RA Tse C.M., Sud K., Zachos N.C., Sarker R., Zhu X., Muise A.M., Zimmer K.P.,
RA Witt H., Zoller H., Donowitz M., Mueller T.;
RT "Reduced sodium/proton exchanger NHE3 activity causes congenital sodium
RT diarrhea.";
RL Hum. Mol. Genet. 24:6614-6623(2015).
CC -!- FUNCTION: Involved in pH regulation to eliminate acids generated by
CC active metabolism or to counter adverse environmental conditions. Major
CC proton extruding system driven by the inward sodium ion chemical
CC gradient (PubMed:26358773). Plays an important role in signal
CC transduction. {ECO:0000269|PubMed:26358773}.
CC -!- SUBUNIT: Binds SLC9A3R1 and SLC9A3R2. Interacts with CHP1, CHP2 and
CC SHANK2. Interacts with PDZK1 (via C-terminal PDZ domain) (By
CC similarity). Interacts with PDZD3 and interactions decrease in response
CC to elevated calcium ion levels. Interacts with AHCYL1; the interaction
CC is required for SLC9A3 activity (PubMed:18829453, PubMed:20584908).
CC {ECO:0000250|UniProtKB:P26432, ECO:0000250|UniProtKB:P26433,
CC ECO:0000250|UniProtKB:Q28362, ECO:0000269|PubMed:18829453,
CC ECO:0000269|PubMed:19088451, ECO:0000269|PubMed:20584908}.
CC -!- INTERACTION:
CC P48764; Q6P0Q8: MAST2; NbExp=2; IntAct=EBI-7816923, EBI-493777;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000269|PubMed:19088451, ECO:0000269|PubMed:26358773}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:19088451}. Note=In intestinal
CC epithelial cells, localizes to the ileal brush border. Phosphorylation
CC at Ser-663 by SGK1 is associated with increased abundance at the cell
CC membrane. Angiotensin-2 enhances apical expression (By similarity).
CC {ECO:0000250|UniProtKB:Q28362}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P48764-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P48764-2; Sequence=VSP_053989;
CC -!- PTM: Phosphorylated by PKA, which inhibits activity. Phosphorylation at
CC Ser-663 by SGK1 is associated with increased abundance at the cell
CC membrane. {ECO:0000250|UniProtKB:P26432, ECO:0000250|UniProtKB:P26433}.
CC -!- DISEASE: Diarrhea 8, secretory sodium, congenital (DIAR8) [MIM:616868]:
CC A disease characterized by watery secretory diarrhea with prenatal
CC onset, prominent abdominal distension after birth due to dilated fluid-
CC filled loops of intestine, elevated fecal sodium concentrations and low
CC urinary sodium concentrations. {ECO:0000269|PubMed:26358773}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the monovalent cation:proton antiporter 1 (CPA1)
CC transporter (TC 2.A.36) family. {ECO:0000305}.
CC -!- CAUTION: The number, localization and denomination of hydrophobic
CC domains in the Na(+)/H(+) exchangers vary among authors. {ECO:0000305}.
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DR EMBL; U28043; AAB48990.1; -; mRNA.
DR EMBL; AC010442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC106772; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC101669; AAI01670.1; -; mRNA.
DR EMBL; BC101671; AAI01672.1; -; mRNA.
DR EMBL; BC143328; AAI43329.1; -; mRNA.
DR CCDS; CCDS3855.1; -. [P48764-1]
DR CCDS; CCDS64116.1; -. [P48764-2]
DR PIR; B40205; B40205.
DR RefSeq; NP_001271280.1; NM_001284351.2. [P48764-2]
DR RefSeq; NP_004165.2; NM_004174.3. [P48764-1]
DR AlphaFoldDB; P48764; -.
DR SMR; P48764; -.
DR BioGRID; 112440; 14.
DR CORUM; P48764; -.
DR IntAct; P48764; 1.
DR MINT; P48764; -.
DR STRING; 9606.ENSP00000264938; -.
DR BindingDB; P48764; -.
DR ChEMBL; CHEMBL3273; -.
DR DrugBank; DB11761; Tenapanor.
DR DrugCentral; P48764; -.
DR TCDB; 2.A.36.1.15; the monovalent cation:proton antiporter-1 (cpa1) family.
DR GlyGen; P48764; 2 sites.
DR iPTMnet; P48764; -.
DR PhosphoSitePlus; P48764; -.
DR BioMuta; SLC9A3; -.
DR DMDM; 269849652; -.
DR jPOST; P48764; -.
DR MassIVE; P48764; -.
DR PaxDb; P48764; -.
DR PeptideAtlas; P48764; -.
DR PRIDE; P48764; -.
DR ProteomicsDB; 20040; -.
DR ProteomicsDB; 55946; -. [P48764-1]
DR Antibodypedia; 22241; 324 antibodies from 26 providers.
DR DNASU; 6550; -.
DR Ensembl; ENST00000264938.8; ENSP00000264938.3; ENSG00000066230.12. [P48764-1]
DR Ensembl; ENST00000514375.1; ENSP00000422983.1; ENSG00000066230.12. [P48764-2]
DR GeneID; 6550; -.
DR KEGG; hsa:6550; -.
DR MANE-Select; ENST00000264938.8; ENSP00000264938.3; NM_004174.4; NP_004165.2.
DR UCSC; uc003jbe.3; human. [P48764-1]
DR CTD; 6550; -.
DR DisGeNET; 6550; -.
DR GeneCards; SLC9A3; -.
DR HGNC; HGNC:11073; SLC9A3.
DR HPA; ENSG00000066230; Tissue enhanced (gallbladder, intestine, kidney, stomach).
DR MalaCards; SLC9A3; -.
DR MIM; 182307; gene.
DR MIM; 616868; phenotype.
DR neXtProt; NX_P48764; -.
DR OpenTargets; ENSG00000066230; -.
DR Orphanet; 103908; Congenital sodium diarrhea.
DR Orphanet; 586; Cystic fibrosis.
DR PharmGKB; PA316; -.
DR VEuPathDB; HostDB:ENSG00000066230; -.
DR eggNOG; KOG1966; Eukaryota.
DR GeneTree; ENSGT00940000158616; -.
DR HOGENOM; CLU_005912_4_2_1; -.
DR InParanoid; P48764; -.
DR OMA; DYEAEEM; -.
DR OrthoDB; 389547at2759; -.
DR PhylomeDB; P48764; -.
DR TreeFam; TF317212; -.
DR PathwayCommons; P48764; -.
DR Reactome; R-HSA-425986; Sodium/Proton exchangers.
DR SignaLink; P48764; -.
DR SIGNOR; P48764; -.
DR BioGRID-ORCS; 6550; 18 hits in 1070 CRISPR screens.
DR GeneWiki; Sodium%E2%80%93hydrogen_antiporter_3; -.
DR GenomeRNAi; 6550; -.
DR Pharos; P48764; Tclin.
DR PRO; PR:P48764; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; P48764; protein.
DR Bgee; ENSG00000066230; Expressed in mucosa of transverse colon and 90 other tissues.
DR ExpressionAtlas; P48764; baseline and differential.
DR Genevisible; P48764; HS.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0005903; C:brush border; ISS:UniProtKB.
DR GO; GO:0031526; C:brush border membrane; ISS:UniProtKB.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0030165; F:PDZ domain binding; ISS:UniProtKB.
DR GO; GO:0015386; F:potassium:proton antiporter activity; IBA:GO_Central.
DR GO; GO:0015385; F:sodium:proton antiporter activity; IDA:UniProtKB.
DR GO; GO:0006811; P:ion transport; TAS:Reactome.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IBA:GO_Central.
DR GO; GO:0051453; P:regulation of intracellular pH; IBA:GO_Central.
DR GO; GO:0098719; P:sodium ion import across plasma membrane; IDA:UniProtKB.
DR InterPro; IPR006153; Cation/H_exchanger.
DR InterPro; IPR018422; Cation/H_exchanger_CPA1.
DR InterPro; IPR018410; Na/H_exchanger_3/5.
DR InterPro; IPR004709; NaH_exchanger.
DR PANTHER; PTHR10110; PTHR10110; 1.
DR Pfam; PF00999; Na_H_Exchanger; 1.
DR PRINTS; PR01084; NAHEXCHNGR.
DR PRINTS; PR01087; NAHEXCHNGR3.
DR TIGRFAMs; TIGR00840; b_cpa1; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Antiport; Cell membrane; Disease variant;
KW Glycoprotein; Ion transport; Membrane; Phosphoprotein; Reference proteome;
KW Sodium; Sodium transport; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..834
FT /note="Sodium/hydrogen exchanger 3"
FT /id="PRO_0000052356"
FT TOPO_DOM 1..12
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT INTRAMEM 13..24
FT /note="Name=A/M1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 25..54
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT INTRAMEM 55..73
FT /note="Name=B/M2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 74..79
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 80..99
FT /note="Helical; Name=C/M3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 100..112
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 113..133
FT /note="Helical; Name=D/M4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 134..139
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 140..160
FT /note="Helical; Name=E/M5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 161..180
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 181..202
FT /note="Helical; Name=F/M5A"
FT /evidence="ECO:0000255"
FT TOPO_DOM 203..210
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 211..232
FT /note="Helical; Name=G/M5B"
FT /evidence="ECO:0000255"
FT TOPO_DOM 233..252
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 253..274
FT /note="Helical; Name=H/M6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 275..290
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 291..309
FT /note="Helical; Name=I/M7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 310..340
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 341..362
FT /note="Helical; Name=J/M8"
FT /evidence="ECO:0000255"
FT TOPO_DOM 363..369
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 370..390
FT /note="Helical; Name=K/M9"
FT /evidence="ECO:0000255"
FT TOPO_DOM 391..405
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT INTRAMEM 406..426
FT /note="Name=L"
FT /evidence="ECO:0000255"
FT TOPO_DOM 427..435
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 436..456
FT /note="Helical; Name=M/M10"
FT /evidence="ECO:0000255"
FT TOPO_DOM 457..834
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 590..667
FT /note="Interaction with PDZD3"
FT /evidence="ECO:0000250"
FT REGION 679..728
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 814..834
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 555
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P26433"
FT MOD_RES 563
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P26433"
FT MOD_RES 592
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:G3X939"
FT MOD_RES 607
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P26433"
FT MOD_RES 663
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0000250|UniProtKB:P26432"
FT MOD_RES 810
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:G3X939"
FT MOD_RES 813
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:G3X939"
FT CARBOHYD 241
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 326
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 452..460
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_053989"
FT VARIANT 127
FT /note="A -> T (in DIAR8; unknown pathological significance;
FT does not affect cell membrane localization; reduces weakly
FT Na(+)/H(+) exchange activity; dbSNP:rs1047334552)"
FT /evidence="ECO:0000269|PubMed:26358773"
FT /id="VAR_076419"
FT VARIANT 269
FT /note="A -> T (in DIAR8; decreases cell membrane
FT expression; reduces Na(+)/H(+) exchange activity;
FT dbSNP:rs869312807)"
FT /evidence="ECO:0000269|PubMed:26358773"
FT /id="VAR_076420"
FT VARIANT 311
FT /note="A -> V (in DIAR8; decreases cell membrane
FT expression; reduces strongly Na(+)/H(+) exchange activity;
FT dbSNP:rs869312806)"
FT /evidence="ECO:0000269|PubMed:26358773"
FT /id="VAR_076421"
FT VARIANT 382
FT /note="R -> Q (in DIAR8; decreases cell membrane
FT localization; reduces strongly Na(+)/H(+) exchange
FT activity; dbSNP:rs766076524)"
FT /evidence="ECO:0000269|PubMed:26358773"
FT /id="VAR_076422"
FT VARIANT 799
FT /note="C -> R (in dbSNP:rs2247114)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:7631746"
FT /id="VAR_060593"
SQ SEQUENCE 834 AA; 92855 MW; 3E7CE3267F6E86F7 CRC64;
MWGLGARGPD RGLLLALALG GLARAGGVEV EPGGAHGESG GFQVVTFEWA HVQDPYVIAL
WILVASLAKI GFHLSHKVTS VVPESALLIV LGLVLGGIVW AADHIASFTL TPTVFFFYLL
PPIVLDAGYF MPNRLFFGNL GTILLYAVVG TVWNAATTGL SLYGVFLSGL MGDLQIGLLD
FLLFGSLMAA VDPVAVLAVF EEVHVNEVLF IIVFGESLLN DAVTVVLYNV FESFVALGGD
NVTGVDCVKG IVSFFVVSLG GTLVGVVFAF LLSLVTRFTK HVRIIEPGFV FIISYLSYLT
SEMLSLSAIL AITFCGICCQ KYVKANISEQ SATTVRYTMK MLASSAETII FMFLGISAVN
PFIWTWNTAF VLLTLVFISV YRAIGVVLQT WLLNRYRMVQ LEPIDQVVLS YGGLRGAVAF
ALVVLLDGDK VKEKNLFVST TIIVVFFTVI FQGLTIKPLV QWLKVKRSEH REPRLNEKLH
GRAFDHILSA IEDISGQIGH NYLRDKWSHF DRKFLSRVLM RRSAQKSRDR ILNVFHELNL
KDAISYVAEG ERRGSLAFIR SPSTDNVVNV DFTPRSSTVE ASVSYLLREN VSAVCLDMQS
LEQRRRSIRD AEDMVTHHTL QQYLYKPRQE YKHLYSRHEL TPTEDEKQDR EIFHRTMRKR
LESFKSTKLG LNQNKKAAKL YKRERAQKRR NSSIPNGKLP MESPAQNFTI KEKDLELSDT
EEPPNYDEEM SGGIEFLASV TKDTASDSPA GIDNPVFSPD EALDRSLLAR LPPWLSPGET
VVPSQRARTQ IPYSPGTFCR LMPFRLSSKS VDSFLQADGP EERPPAALPE STHM
