ID   SL9A4_RAT               Reviewed;         717 AA.
AC   P26434;
DT   01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1992, sequence version 1.
DT   27-MAR-2024, entry version 146.
DE   RecName: Full=Sodium/hydrogen exchanger 4;
DE   AltName: Full=Na(+)/H(+) exchanger 4;
DE            Short=NHE-4;
DE   AltName: Full=Solute carrier family 9 member 4;
GN   Name=Slc9a4; Synonyms=Nhe4;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC   STRAIN=Sprague-Dawley; TISSUE=Stomach;
RX   PubMed=1577762; DOI=10.1016/s0021-9258(19)50428-8;
RA   Orlowski J., Kandasamy R.A., Shull G.E.;
RT   "Molecular cloning of putative members of the Na/H exchanger gene family.
RT   cDNA cloning, deduced amino acid sequence, and mRNA tissue expression of
RT   the rat Na/H exchanger NHE-1 and two structurally related proteins.";
RL   J. Biol. Chem. 267:9331-9339(1992).
RN   [2]
RP   FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=7961960; DOI=10.1016/s0021-9258(18)43937-3;
RA   Bookstein C., Musch M.W., DePaoli A., Xie Y., Villereal M., Rao M.C.,
RA   Chang E.B.;
RT   "A unique sodium-hydrogen exchange isoform (NHE-4) of the inner medulla of
RT   the rat kidney is induced by hyperosmolarity.";
RL   J. Biol. Chem. 269:29704-29709(1994).
RN   [3]
RP   FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=8944646; DOI=10.1152/ajpcell.1996.271.5.c1629;
RA   Bookstein C., Musch M.W., DePaoli A., Xie Y., Rabenau K., Villereal M.,
RA   Rao M.C., Chang E.B.;
RT   "Characterization of the rat Na+/H+ exchanger isoform NHE4 and localization
RT   in rat hippocampus.";
RL   Am. J. Physiol. 271:C1629-C1638(1996).
RN   [4]
RP   FUNCTION, TRANSPORTER ACTIVITY, AND ACTIVITY REGULATION.
RX   PubMed=9038815; DOI=10.1152/ajpcell.1997.272.1.c90;
RA   Chambrey R., Achard J.-M., Warnock D.G.;
RT   "Heterologous expression of rat NHE4: a highly amiloride-resistant Na+/H+
RT   exchanger isoform.";
RL   Am. J. Physiol. 272:C90-C98(1997).
RN   [5]
RP   TISSUE SPECIFICITY.
RX   PubMed=9374634; DOI=10.1152/ajpcell.1997.273.5.c1496;
RA   Bookstein C., Xie Y., Rabenau K., Musch M.W., McSwine R.L., Rao M.C.,
RA   Chang E.B.;
RT   "Tissue distribution of Na+/H+ exchanger isoforms NHE2 and NHE4 in rat
RT   intestine and kidney.";
RL   Am. J. Physiol. 273:C1496-C1505(1997).
RN   [6]
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=9755122; DOI=10.1152/ajprenal.1998.275.4.f510;
RA   Pizzonia J.H., Biemesderfer D., Abu-Alfa A.K., Wu M.-S., Exner M.,
RA   Isenring P., Igarashi P., Aronson P.S.;
RT   "Immunochemical characterization of Na+/H+ exchanger isoform NHE4.";
RL   Am. J. Physiol. 275:F510-F517(1998).
RN   [7]
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=9610358; DOI=10.1006/bbrc.1998.8611;
RA   Anderie I., Blum R., Haase W., Grinstein S., Thevenod F.;
RT   "Expression of NHE1 and NHE4 in rat pancreatic zymogen granule membranes.";
RL   Biochem. Biophys. Res. Commun. 246:330-336(1998).
RN   [8]
RP   TISSUE SPECIFICITY.
RX   PubMed=9691122; DOI=10.1007/s002329900414;
RA   Sun A.M., Liu Y., Centracchio J., Dworkin L.D.;
RT   "Expression of Na+/H+ exchanger isoforms in inner segment of inner
RT   medullary collecting duct.";
RL   J. Membr. Biol. 164:293-300(1998).
RN   [9]
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=11553518; DOI=10.1152/ajprenal.2001.281.4.f707;
RA   Chambrey R., St John P.L., Eladari D., Quentin F., Warnock D.G.,
RA   Abrahamson D.R., Podevin R.-A., Paillard M.;
RT   "Localization and functional characterization of Na+/H+ exchanger isoform
RT   NHE4 in rat thick ascending limbs.";
RL   Am. J. Physiol. 281:F707-F717(2001).
RN   [10]
RP   INTERACTION WITH CHP1 AND CHP2.
RX   PubMed=12576672; DOI=10.1248/bpb.26.148;
RA   Inoue H., Nakamura Y., Nagita M., Takai T., Masuda M., Nakamura N.,
RA   Kanazawa H.;
RT   "Calcineurin homologous protein isoform 2 (CHP2), Na+/H+ exchangers-binding
RT   protein, is expressed in intestinal epithelium.";
RL   Biol. Pharm. Bull. 26:148-155(2003).
RN   [11]
RP   TISSUE SPECIFICITY.
RX   PubMed=16158325; DOI=10.1007/s00441-005-0055-6;
RA   Oehlke O., Sprysch P., Rickmann M., Roussa E.;
RT   "Na(+)/H(+) exchanger isoforms are differentially regulated in rat
RT   submandibular gland during acid/base disturbances in vivo.";
RL   Cell Tissue Res. 323:253-262(2006).
CC   -!- FUNCTION: Electroneutral antiporter that exchanges sodium for protons
CC       or ammonium ions at the basolateral membrane of epithelia to regulate
CC       cell volume and intracellular pH upon hypertonic conditions
CC       (PubMed:7961960, PubMed:8944646, PubMed:9038815). As part of
CC       transcellular ammonia transport in renal tubules, mediates basolateral
CC       ammonium extrusion in the medullary thick ascending limb, regulating
CC       the corticopapillary ammonium gradient and overall renal acid excretion
CC       (By similarity). Mediates sodium:proton exchange in gastric parietal
CC       cells secondary to cAMP-dependent acid secretion and hyperosmolarity.
CC       Possibly coupled to chloride:bicarbonate antiporter, enables loading of
CC       parietal cells with sodium and chloride ions to maintain cell volume
CC       and normal gastric acid secretion (By similarity). Functions as a
CC       sodium sensor in neurons of organum vasculosum of the lamina terminalis
CC       where it regulates water intake in response to increased sodium
CC       concentration in body fluids (By similarity).
CC       {ECO:0000250|UniProtKB:Q8BUE1, ECO:0000269|PubMed:7961960,
CC       ECO:0000269|PubMed:8944646, ECO:0000269|PubMed:9038815}.
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:7961960, ECO:0000269|PubMed:8944646,
CC         ECO:0000269|PubMed:9038815};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:29421;
CC         Evidence={ECO:0000250|UniProtKB:Q8BUE1};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Na(+)(out) + NH4(+)(in) = Na(+)(in) + NH4(+)(out);
CC         Xref=Rhea:RHEA:76431, ChEBI:CHEBI:28938, ChEBI:CHEBI:29101;
CC         Evidence={ECO:0000250|UniProtKB:Q8BUE1};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76432;
CC         Evidence={ECO:0000250|UniProtKB:Q8BUE1};
CC   -!- ACTIVITY REGULATION: Activated upon hypertonic conditions. Insensitive
CC       to amiloride, a common inhibitor of sodium:proton exchangers. Inhibited
CC       by certain amiloride analogs such as 5-(N,N-hexamethylene)amiloride
CC       (HMA) and 5-(N,N-dimethyl)amiloride (DMA). Resistant to 5-(N-ethyl-N-
CC       isopropyl)amiloride (EIPA) and cimetidine inhibitors when compared to
CC       SLC9A1. Activated by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid
CC       (DIDS). {ECO:0000269|PubMed:7961960, ECO:0000269|PubMed:8944646,
CC       ECO:0000269|PubMed:9038815}.
CC   -!- SUBUNIT: Homodimer; each protomer has one site for sodium and one site
CC       for proton binding (By similarity). Interacts with CHP1 and CHP2
CC       (PubMed:12576672). {ECO:0000250|UniProtKB:P19634,
CC       ECO:0000269|PubMed:12576672}.
CC   -!- SUBCELLULAR LOCATION: Basolateral cell membrane
CC       {ECO:0000269|PubMed:11553518, ECO:0000269|PubMed:9755122}; Multi-pass
CC       membrane protein {ECO:0000255}. Apical cell membrane
CC       {ECO:0000250|UniProtKB:Q8BUE1}; Multi-pass membrane protein
CC       {ECO:0000255}. Zymogen granule membrane {ECO:0000269|PubMed:9610358};
CC       Multi-pass membrane protein {ECO:0000255}. Note=Enrichment at apical or
CC       basolateral membrane may be tissue-dependent.
CC       {ECO:0000305|PubMed:11553518, ECO:0000305|PubMed:9755122}.
CC   -!- TISSUE SPECIFICITY: Most abundant in stomach, followed by colon. Lesser
CC       amounts were found in kidney, liver, brain, uterus and skeletal muscle.
CC       Predominantly expressed in the inner segments of inner medullary
CC       collecting ducts (IMCD) in kidney. Highly expressed in the cavi amnoni
CC       fields of hippocampus. Expressed in pancreas. Expressed in multiple
CC       nephron segments including proximla tubules, medullar thick ascending
CC       limbs (MTAL), cortical thick ascending limbs (CTAL), distal covoluted
CC       tubules and cortical and medullary collecting ducts. Expressed in
CC       submandibular gland. {ECO:0000269|PubMed:11553518,
CC       ECO:0000269|PubMed:1577762, ECO:0000269|PubMed:16158325,
CC       ECO:0000269|PubMed:7961960, ECO:0000269|PubMed:8944646,
CC       ECO:0000269|PubMed:9374634, ECO:0000269|PubMed:9610358,
CC       ECO:0000269|PubMed:9691122, ECO:0000269|PubMed:9755122}.
CC   -!- PTM: May be phosphorylated.
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; M85301; AAA41703.1; -; mRNA.
DR   PIR; C40204; C40204.
DR   RefSeq; NP_775121.1; NM_173098.1.
DR   AlphaFoldDB; P26434; -.
DR   SMR; P26434; -.
DR   IntAct; P26434; 2.
DR   STRING; 10116.ENSRNOP00000059258; -.
DR   GlyCosmos; P26434; 1 site, No reported glycans.
DR   GlyGen; P26434; 1 site.
DR   iPTMnet; P26434; -.
DR   PhosphoSitePlus; P26434; -.
DR   PaxDb; 10116-ENSRNOP00000059258; -.
DR   KEGG; rno:24785; -.
DR   UCSC; RGD:3721; rat.
DR   AGR; RGD:3721; -.
DR   CTD; 389015; -.
DR   RGD; 3721; Slc9a4.
DR   eggNOG; KOG1966; Eukaryota.
DR   InParanoid; P26434; -.
DR   OrthoDB; 1065060at2759; -.
DR   Reactome; R-RNO-425986; Sodium/Proton exchangers.
DR   PRO; PR:P26434; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0042589; C:zymogen granule membrane; IEA:UniProtKB-SubCell.
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:0001696; P:gastric acid secretion; ISO:RGD.
DR   GO; GO:0002068; P:glandular epithelial cell development; ISO:RGD.
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; IBA:GO_Central.
DR   GO; GO:0070634; P:transepithelial ammonium transport; ISS:UniProtKB.
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   NCBIfam; TIGR00840; b_cpa1; 1.
DR   PANTHER; PTHR10110; SODIUM/HYDROGEN EXCHANGER; 1.
DR   PANTHER; PTHR10110:SF103; SODIUM_HYDROGEN EXCHANGER 4; 1.
DR   Pfam; PF00999; Na_H_Exchanger; 1.
DR   Pfam; PF16644; NEXCaM_BD; 1.
DR   PRINTS; PR01084; NAHEXCHNGR.
DR   PRINTS; PR01086; NAHEXCHNGR2.
PE   1: Evidence at protein level;
KW   Antiport; Cell membrane; Cytoplasmic vesicle; Glycoprotein; Ion transport;
KW   Membrane; Phosphoprotein; Reference proteome; Sodium; Sodium transport;
KW   Transmembrane; Transmembrane helix; Transport.
FT   CHAIN           1..717
FT                   /note="Sodium/hydrogen exchanger 4"
FT                   /id="PRO_0000052359"
FT   TOPO_DOM        1..13
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   INTRAMEM        14..28
FT                   /note="Name=A/M1"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        29..69
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   INTRAMEM        70..90
FT                   /note="Name=B/M2"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        91..94
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        95..114
FT                   /note="Helical; Name=C/M3"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        115..127
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        128..148
FT                   /note="Helical; Name=D/M4"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        149..154
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        155..175
FT                   /note="Helical; Name=E/M5"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        176..191
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        192..216
FT                   /note="Helical; Name=F/M5A"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        217..225
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        226..247
FT                   /note="Helical; Name=G/M5B"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        248..269
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        270..290
FT                   /note="Helical; Name=H/M6"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        291..304
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        305..325
FT                   /note="Helical; Name=I/M7"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        326..356
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        357..377
FT                   /note="Helical; Name=J/M8"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        378..384
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        385..405
FT                   /note="Helical; Name=K/M9"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        406..420
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   INTRAMEM        421..441
FT                   /note="Name=L"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        442..450
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        451..471
FT                   /note="Helical; Name=M/M10"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        472..717
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        342
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
SQ   SEQUENCE   717 AA;  81522 MW;  4EFBBEC7D7782753 CRC64;
     MGPAMLRAFS SWKWLLLLMV LTCLEASSYV NESSSPTGQQ TPDARFAASS SDPDERISVF
     ELDYDYVQIP YEVTLWILLA SLAKIGFHLY HRLPHLMPES CLLIIVGALV GSIIFGTHHK
     SPPVMDSSIY FLYLLPPIVL ESGYFMPTRP FFENIGSILW WAGLGALINA FGIGLSLYFI
     CQIKAFGLGD INLLQNLLFG SLISAVDPVA VLAVFEEARV NEQLYMMIFG EALLNDGISV
     VLYNILIAFT KMHKFEDIEA VDILAGCARF VIVGCGGVFF GIIFGFISAF ITRFTQNISA
     IEPLIVFMFS YLSYLAAETL YLSGILAITA CAVTMKKYVE ENVSQTSYTT IKYFMKMLSS
     VSETLIFIFM GVSTVGKNHE WNWAFVCFTL AFCQIWRAIS VFTLFYVSNQ FRTFPFSIKD
     QLIIFYSGVR GAGSFSLAFL LPLTLFPRKK LFVTATLVVT YFTVFFQGIT IGPLVRYLDV
     RKTNKKESIN EELHIRLMDH LKAGIEDVCG QWSHYQVRDK FKKFDHRYLR KILIRRNQPK
     SSIVSLYKKL EMKQAIEMAE TGLLSSVASP TPYQSERIQG IKRLSPEDVE SMRDILTRNM
     YQVRQRTLSY NKYNLKPQTS EKQAKEILIR RQNTLRESLR KGQSLPWVKP AGTKNFRYLS
     FPYSNPQPAR RGARAAESTG NPCCWLLHFL LCRAMVEKIW GPGGQETQPR LLCRNLN
//