SL9A4_RAT
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 03-AUG-2022, entry version 139.
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, TISSUE SPECIFICITY, AND INDUCTION.
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, AND TISSUE 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.
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: 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. Plays an important role in signal transduction. May play a
CC specialized role in the kidney in rectifying cell volume in response to
CC extreme fluctuations of hyperosmolar-stimulated cell shrinkage. Is
CC relatively amiloride and ethylisopropylamiloride (EIPA) insensitive.
CC Can be activated under conditions of hyperosmolar-induced cell
CC shrinkage in a sustained intracellular acidification-dependence manner.
CC Activated by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) in
CC a sustained intracellular acidification-dependence manner. Affects
CC potassium/proton exchange as well as sodium/proton and lithium/proton
CC exchange. In basolateral cell membrane, participates in homeostatic
CC control of intracellular pH, and may play a role in proton extrusion in
CC order to achieve transepithelial HCO3(-) secretion. In apical cell
CC membrane may be involved in mediating sodium absorption. Requires for
CC normal levels of gastric acid secretion, secretory membrane
CC development, parietal cell maturation and/or differentiation and at
CC least secondarily for chief cell differentiation.
CC {ECO:0000269|PubMed:7961960, ECO:0000269|PubMed:8944646,
CC ECO:0000269|PubMed:9038815}.
CC -!- SUBUNIT: Interacts with CHP1 and CHP2. {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 GlyGen; P26434; 1 site.
DR iPTMnet; P26434; -.
DR PhosphoSitePlus; P26434; -.
DR PaxDb; P26434; -.
DR GeneID; 24785; -.
DR KEGG; rno:24785; -.
DR UCSC; RGD:3721; rat.
DR CTD; 389015; -.
DR RGD; 3721; Slc9a4.
DR eggNOG; KOG1966; Eukaryota.
DR InParanoid; P26434; -.
DR OrthoDB; 316731at2759; -.
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; IEA:UniProtKB-SubCell.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005774; C:vacuolar membrane; IEA:InterPro.
DR GO; GO:0015386; F:potassium:proton antiporter activity; IBA:GO_Central.
DR GO; GO:0015385; F:sodium:proton antiporter activity; IBA:GO_Central.
DR GO; GO:0002064; P:epithelial cell development; ISO:RGD.
DR GO; GO:0001696; P:gastric acid secretion; ISO:RGD.
DR GO; GO:0055075; P:potassium ion homeostasis; IEA:InterPro.
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:0009651; P:response to salt stress; IEA:InterPro.
DR GO; GO:0098719; P:sodium ion import across plasma membrane; IBA:GO_Central.
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; IPR036958; NHE-4.
DR InterPro; IPR032103; NHE_CaM-bd.
DR PANTHER; PTHR10110; PTHR10110; 1.
DR PANTHER; PTHR10110:SF103; PTHR10110:SF103; 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; 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
