SL9A4_MOUSE
ID SL9A4_MOUSE Reviewed; 797 AA.
AC Q8BUE1; Q3TCU9; Q9WUJ6;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 138.
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 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 MRNA].
RC STRAIN=C57BL/6J; TISSUE=Hippocampus, and Mammary gland;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 304-498.
RC STRAIN=C57BL/6J; TISSUE=Kidney;
RX PubMed=10666043; DOI=10.1152/ajpgi.2000.278.2.g197;
RA Praetorius J., Andreasen D., Jensen B.L., Ainsworth M.A., Friis U.G.,
RA Johansen T.;
RT "NHE1, NHE2, and NHE3 contribute to regulation of intracellular pH in
RT murine duodenal epithelial cells.";
RL Am. J. Physiol. 278:G197-G206(2000).
RN [4]
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 [5]
RP SPECIFICITY.
RX PubMed=11880326; DOI=10.1152/ajprenal.00291.2000;
RA Hill C., Giesberts A.N., White S.J.;
RT "Expression of isoforms of the Na(+)/H(+) exchanger in M-1 mouse cortical
RT collecting duct cells.";
RL Am. J. Physiol. 282:F649-F654(2002).
RN [6]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=12493726; DOI=10.1095/biolreprod.102.005645;
RA Wang X.F., Yu M.K., Lam S.Y., Leung K.M., Jiang J.L., Leung P.S., Ko W.H.,
RA Leung P.Y., Chew S.B.C., Liu C.Q., Tse C.M., Chan H.C.;
RT "Expression, immunolocalization, and functional activity of Na+/H+
RT exchanger isoforms in mouse endometrial epithelium.";
RL Biol. Reprod. 68:302-308(2003).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15684419; DOI=10.1074/jbc.m414118200;
RA Gawenis L.R., Greeb J.M., Prasad V., Grisham C., Sanford L.P.,
RA Doetschman T., Andringa A., Miller M.L., Shull G.E.;
RT "Impaired gastric acid secretion in mice with a targeted disruption of the
RT NHE4 Na+/H+ exchanger.";
RL J. Biol. Chem. 280:12781-12789(2005).
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 (By similarity). In basolateral cell membrane, participates in
CC homeostatic control of intracellular pH, and may play a role in proton
CC extrusion in order to achieve transepithelial HCO3(-) secretion. In
CC apical cell membrane may be involved in mediating sodium absorption.
CC Requires for normal levels of gastric acid secretion, secretory
CC membrane development, parietal cell maturation and/or differentiation
CC and at least secondarily for chief cell differentiation. {ECO:0000250,
CC ECO:0000269|PubMed:12493726, ECO:0000269|PubMed:15684419}.
CC -!- SUBUNIT: Interacts with CHP1 and CHP2. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Basolateral cell membrane
CC {ECO:0000269|PubMed:12493726}; Multi-pass membrane protein
CC {ECO:0000255}. Apical cell membrane {ECO:0000269|PubMed:12493726};
CC Multi-pass membrane protein {ECO:0000255}. Zymogen granule membrane
CC {ECO:0000250|UniProtKB:P26434}; Multi-pass membrane protein
CC {ECO:0000255}. Note=Enrichment at apical or basolateral membrane may be
CC tissue-dependent. {ECO:0000305|PubMed:12493726}.
CC -!- TISSUE SPECIFICITY: Expressed in kidney. Expressed in uterus and
CC endometrial epithelial cells. Expressed in the inner segments of inner
CC medullary collecting ducts (IMCD) in kidney.
CC {ECO:0000269|PubMed:9691122}.
CC -!- PTM: May be phosphorylated. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Mice survive and appear outwardly normal.
CC Analysis of their stomach contents reveals that mice are
CC hypochlorhydric. Their gastric mucosa reveal an sharply reduced numbers
CC of parietal cell, a loss of mature chief cells, an increased numbers of
CC mucous and undifferentiation cells and an increase in the number of
CC necrotic and apoptotic cells. Parietal cells exhibit limited
CC development of canalicular membranes and a virtual absence of
CC tubulovesicles and some of the microvilli had centrally bundled actin.
CC {ECO:0000269|PubMed:15684419}.
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; AK085681; BAC39504.1; -; mRNA.
DR EMBL; AK141534; BAE24721.1; -; mRNA.
DR EMBL; AK170522; BAE41856.1; -; mRNA.
DR EMBL; BC120543; AAI20544.1; -; mRNA.
DR EMBL; AF139195; AAD30297.1; -; mRNA.
DR CCDS; CCDS14913.1; -.
DR RefSeq; NP_796058.1; NM_177084.3.
DR AlphaFoldDB; Q8BUE1; -.
DR SMR; Q8BUE1; -.
DR STRING; 10090.ENSMUSP00000027233; -.
DR GlyGen; Q8BUE1; 1 site.
DR iPTMnet; Q8BUE1; -.
DR PhosphoSitePlus; Q8BUE1; -.
DR PaxDb; Q8BUE1; -.
DR PRIDE; Q8BUE1; -.
DR ProteomicsDB; 257194; -.
DR Antibodypedia; 49172; 10 antibodies from 6 providers.
DR DNASU; 110895; -.
DR Ensembl; ENSMUST00000027233; ENSMUSP00000027233; ENSMUSG00000026065.
DR GeneID; 110895; -.
DR KEGG; mmu:110895; -.
DR UCSC; uc007aul.1; mouse.
DR CTD; 389015; -.
DR MGI; MGI:105074; Slc9a4.
DR VEuPathDB; HostDB:ENSMUSG00000026065; -.
DR eggNOG; KOG1966; Eukaryota.
DR GeneTree; ENSGT00940000160774; -.
DR HOGENOM; CLU_005912_4_3_1; -.
DR InParanoid; Q8BUE1; -.
DR OMA; TFSPWNC; -.
DR OrthoDB; 316731at2759; -.
DR PhylomeDB; Q8BUE1; -.
DR TreeFam; TF317212; -.
DR Reactome; R-MMU-425986; Sodium/Proton exchangers.
DR BioGRID-ORCS; 110895; 2 hits in 71 CRISPR screens.
DR PRO; PR:Q8BUE1; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q8BUE1; protein.
DR Bgee; ENSMUSG00000026065; Expressed in stomach and 36 other tissues.
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:0001696; P:gastric acid secretion; IMP:MGI.
DR GO; GO:0002068; P:glandular epithelial cell development; IMP:MGI.
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 2: Evidence at transcript 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..797
FT /note="Sodium/hydrogen exchanger 4"
FT /id="PRO_0000314666"
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..194
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 195..215
FT /note="Helical; Name=F/M5A"
FT /evidence="ECO:0000255"
FT TOPO_DOM 216..226
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 227..247
FT /note="Helical; Name=G/M5B"
FT /evidence="ECO:0000255"
FT TOPO_DOM 248..270
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 271..291
FT /note="Helical; Name=H/M6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 292..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..352
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 353..373
FT /note="Helical; Name=J/M8"
FT /evidence="ECO:0000255"
FT TOPO_DOM 374..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..797
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 32..52
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 759..797
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 32..46
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 342
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
SQ SEQUENCE 797 AA; 90937 MW; A2205C476FDA92F1 CRC64;
MGPAMFMAFR LWNWLLLLAV LTRSEATSYV NESSNPTAQQ APDARFAASS SDPDEGISVF
ELDYDYVQIP YEVTLWILLA SLAKIGFHLY HRLPHLMPES CLLIIVGALV GGIIFGTHHK
SPPVMDSSIY FLYLLPPIVL ESGYFMPTRP FFENIGSILW WAGLGALINA FGIGLSLYFI
CQIKAFGLGD INLLHNLLFG SLISAVDPVA VLAVFEEARV NEQLYMMIFG EALLNDGISV
VLYNILIAFT KMHKFEDIEA VDILAGCARF VIVGCGGVFF GIIFGFISAF ITRFTQNISA
IEPLIVFMFS YLSYLAAETL YLSGILAITA CAVTMKKYVE ENVSQTSYTT IKYFMKMLSS
VSETLIFIFM GVSTIGKNHE WNWAFICFTL LFCQIWRAIS VFTLFYVSNQ FRTFPFSIKD
QFIIFYSGVR GAGSFSLAFL LPLSLFPRKK LFVTATLVVT YFTVFFQGIT IGPLVRYLDV
RKTNKKESIN EELHSRLMDH LKAGIEDVCG QWSHYQVRDK FKKFDHRYLR KILIRRNLPK
SSIVSLYKKL EMKQAIEMVE TGILSSVASP TPYQSERIQG IKRLSPEDVE SMRDILTRSM
YQVRQRTLSY NKYNLKPQTS EKQAKEILIR RQNTLRESMR KGQSLPWGKP AGTKNFRYLS
FPYSNPQAAR REARAAEPTD DDGTDSGFQP LMFSIHSRAG SLQERRQTQA VIPMKRLQRG
EKALSFSYRS NTSWEDQAGW RRMDVLRPKP LFYAVAEEYD SGEQTEEETS AILSRWTAEH
RHSTEHHKSH SPLLHRK
