Full text data of SLC9A3
SLC9A3
(NHE3)
[Confidence: low (only semi-automatic identification from reviews)]
Sodium/hydrogen exchanger 3 (Na(+)/H(+) exchanger 3; NHE-3; Solute carrier family 9 member 3)
Sodium/hydrogen exchanger 3 (Na(+)/H(+) exchanger 3; NHE-3; Solute carrier family 9 member 3)
UniProt
P48764
ID SL9A3_HUMAN Reviewed; 834 AA.
AC P48764; Q3MIW3;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-NOV-2009, sequence version 2.
DT 22-JAN-2014, entry version 119.
DE RecName: Full=Sodium/hydrogen exchanger 3;
DE AltName: Full=Na(+)/H(+) exchanger 3;
DE Short=NHE-3;
DE AltName: Full=Solute carrier family 9 member 3;
GN Name=SLC9A3; Synonyms=NHE3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ARG-799.
RC TISSUE=Kidney cortex;
RX PubMed=7631746;
RA Brant S.R., Yun C.H., Donowitz M., Tse C.-M.;
RT "Cloning, tissue distribution, and functional analysis of the human
RT Na+/N+ 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.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA 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], AND VARIANT 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
RT project: 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).
CC -!- FUNCTION: Involved in pH regulation to eliminate acids generated
CC by active metabolism or to counter adverse environmental
CC conditions. Major proton extruding system driven by the inward
CC sodium ion chemical gradient. Plays an important role in signal
CC transduction.
CC -!- SUBUNIT: Binds SLC9A3R1 and SLC9A3R2. Interacts with CHP1, CHP2
CC and SHANK2. Interacts with PDZK1 (via C-terminal PDZ domain) (By
CC similarity). Interacts with PDZD3 and interactions decrease in
CC response to elevated calcium ion levels.
CC -!- INTERACTION:
CC Q6P0Q8:MAST2; NbExp=2; IntAct=EBI-7816923, EBI-493777;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane; Multi-pass membrane
CC protein. Note=In intestinal epithelial cells, localizes to the
CC ileal brush border. Phosphorylation at Ser-663 by SGK1 is
CC associated with increased abundance at the cell membrane.
CC -!- PTM: Phosphorylated by PKA, which inhibits activity (By
CC similarity). Phosphorylation at Ser-663 by SGK1 is associated with
CC increased abundance at the cell membrane (By similarity).
CC -!- SIMILARITY: Belongs to the monovalent cation:proton antiporter 1
CC (CPA1) transporter (TC 2.A.36) family.
CC -!- CAUTION: The number, localization and denomination of hydrophobic
CC domains in the Na(+)/H(+) exchangers vary among authors.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
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 PIR; B40205; B40205.
DR RefSeq; NP_001271280.1; NM_001284351.1.
DR RefSeq; NP_004165.2; NM_004174.2.
DR UniGene; Hs.658120; -.
DR ProteinModelPortal; P48764; -.
DR SMR; P48764; 204-229, 294-321, 460-502, 608-666.
DR IntAct; P48764; 1.
DR MINT; MINT-1787470; -.
DR STRING; 9606.ENSP00000264938; -.
DR ChEMBL; CHEMBL3273; -.
DR TCDB; 2.A.36.1.15; the monovalent cation:proton antiporter-1 (cpa1) family.
DR PhosphoSite; P48764; -.
DR DMDM; 269849652; -.
DR PaxDb; P48764; -.
DR PRIDE; P48764; -.
DR Ensembl; ENST00000264938; ENSP00000264938; ENSG00000066230.
DR GeneID; 6550; -.
DR KEGG; hsa:6550; -.
DR UCSC; uc003jbe.2; human.
DR CTD; 6550; -.
DR GeneCards; GC05M000473; -.
DR H-InvDB; HIX0004707; -.
DR H-InvDB; HIX0032039; -.
DR HGNC; HGNC:11073; SLC9A3.
DR HPA; HPA036493; -.
DR HPA; HPA036669; -.
DR MIM; 182307; gene.
DR neXtProt; NX_P48764; -.
DR PharmGKB; PA316; -.
DR eggNOG; COG0025; -.
DR HOGENOM; HOG000247044; -.
DR HOVERGEN; HBG052615; -.
DR InParanoid; P48764; -.
DR KO; K12040; -.
DR OMA; RDKWSNF; -.
DR OrthoDB; EOG7KQ20Z; -.
DR PhylomeDB; P48764; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR GeneWiki; Sodium%E2%80%93hydrogen_antiporter_3; -.
DR GenomeRNAi; 6550; -.
DR NextBio; 25493; -.
DR PRO; PR:P48764; -.
DR ArrayExpress; P48764; -.
DR Bgee; P48764; -.
DR CleanEx; HS_SLC9A3; -.
DR Genevestigator; P48764; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031526; C:brush border membrane; ISS:UniProtKB.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0030165; F:PDZ domain binding; ISS:UniProtKB.
DR GO; GO:0015385; F:sodium:hydrogen antiporter activity; ISS:UniProtKB.
DR GO; GO:0006885; P:regulation of pH; IEA:Ensembl.
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 Antiport; Cell membrane; Complete proteome; Glycoprotein;
KW Ion transport; Membrane; Phosphoprotein; Polymorphism;
KW Reference proteome; Sodium; Sodium transport; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1 834 Sodium/hydrogen exchanger 3.
FT /FTId=PRO_0000052356.
FT TOPO_DOM 1 12 Cytoplasmic (Potential).
FT INTRAMEM 13 24 Name=A/M1; (Potential).
FT TOPO_DOM 25 54 Cytoplasmic (Potential).
FT INTRAMEM 55 73 Name=B/M2; (Potential).
FT TOPO_DOM 74 79 Cytoplasmic (Potential).
FT TRANSMEM 80 99 Helical; Name=C/M3; (Potential).
FT TOPO_DOM 100 112 Extracellular (Potential).
FT TRANSMEM 113 133 Helical; Name=D/M4; (Potential).
FT TOPO_DOM 134 139 Cytoplasmic (Potential).
FT TRANSMEM 140 160 Helical; Name=E/M5; (Potential).
FT TOPO_DOM 161 180 Extracellular (Potential).
FT TRANSMEM 181 202 Helical; Name=F/M5A; (Potential).
FT TOPO_DOM 203 210 Cytoplasmic (Potential).
FT TRANSMEM 211 232 Helical; Name=G/M5B; (Potential).
FT TOPO_DOM 233 252 Extracellular (Potential).
FT TRANSMEM 253 274 Helical; Name=H/M6; (Potential).
FT TOPO_DOM 275 290 Cytoplasmic (Potential).
FT TRANSMEM 291 309 Helical; Name=I/M7; (Potential).
FT TOPO_DOM 310 340 Extracellular (Potential).
FT TRANSMEM 341 362 Helical; Name=J/M8; (Potential).
FT TOPO_DOM 363 369 Cytoplasmic (Potential).
FT TRANSMEM 370 390 Helical; Name=K/M9; (Potential).
FT TOPO_DOM 391 405 Extracellular (Potential).
FT INTRAMEM 406 426 Name=L; (Potential).
FT TOPO_DOM 427 435 Extracellular (Potential).
FT TRANSMEM 436 456 Helical; Name=M/M10; (Potential).
FT TOPO_DOM 457 834 Cytoplasmic (Potential).
FT REGION 590 667 Interaction with PDZD3 (By similarity).
FT MOD_RES 555 555 Phosphoserine (By similarity).
FT MOD_RES 607 607 Phosphoserine (By similarity).
FT MOD_RES 663 663 Phosphoserine; by SGK1.
FT CARBOHYD 241 241 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 326 326 N-linked (GlcNAc...) (Potential).
FT VARIANT 799 799 C -> R (in dbSNP:rs2247114).
FT /FTId=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
//
ID SL9A3_HUMAN Reviewed; 834 AA.
AC P48764; Q3MIW3;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-NOV-2009, sequence version 2.
DT 22-JAN-2014, entry version 119.
DE RecName: Full=Sodium/hydrogen exchanger 3;
DE AltName: Full=Na(+)/H(+) exchanger 3;
DE Short=NHE-3;
DE AltName: Full=Solute carrier family 9 member 3;
GN Name=SLC9A3; Synonyms=NHE3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ARG-799.
RC TISSUE=Kidney cortex;
RX PubMed=7631746;
RA Brant S.R., Yun C.H., Donowitz M., Tse C.-M.;
RT "Cloning, tissue distribution, and functional analysis of the human
RT Na+/N+ 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.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA 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], AND VARIANT 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
RT project: 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).
CC -!- FUNCTION: Involved in pH regulation to eliminate acids generated
CC by active metabolism or to counter adverse environmental
CC conditions. Major proton extruding system driven by the inward
CC sodium ion chemical gradient. Plays an important role in signal
CC transduction.
CC -!- SUBUNIT: Binds SLC9A3R1 and SLC9A3R2. Interacts with CHP1, CHP2
CC and SHANK2. Interacts with PDZK1 (via C-terminal PDZ domain) (By
CC similarity). Interacts with PDZD3 and interactions decrease in
CC response to elevated calcium ion levels.
CC -!- INTERACTION:
CC Q6P0Q8:MAST2; NbExp=2; IntAct=EBI-7816923, EBI-493777;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane; Multi-pass membrane
CC protein. Note=In intestinal epithelial cells, localizes to the
CC ileal brush border. Phosphorylation at Ser-663 by SGK1 is
CC associated with increased abundance at the cell membrane.
CC -!- PTM: Phosphorylated by PKA, which inhibits activity (By
CC similarity). Phosphorylation at Ser-663 by SGK1 is associated with
CC increased abundance at the cell membrane (By similarity).
CC -!- SIMILARITY: Belongs to the monovalent cation:proton antiporter 1
CC (CPA1) transporter (TC 2.A.36) family.
CC -!- CAUTION: The number, localization and denomination of hydrophobic
CC domains in the Na(+)/H(+) exchangers vary among authors.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
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 PIR; B40205; B40205.
DR RefSeq; NP_001271280.1; NM_001284351.1.
DR RefSeq; NP_004165.2; NM_004174.2.
DR UniGene; Hs.658120; -.
DR ProteinModelPortal; P48764; -.
DR SMR; P48764; 204-229, 294-321, 460-502, 608-666.
DR IntAct; P48764; 1.
DR MINT; MINT-1787470; -.
DR STRING; 9606.ENSP00000264938; -.
DR ChEMBL; CHEMBL3273; -.
DR TCDB; 2.A.36.1.15; the monovalent cation:proton antiporter-1 (cpa1) family.
DR PhosphoSite; P48764; -.
DR DMDM; 269849652; -.
DR PaxDb; P48764; -.
DR PRIDE; P48764; -.
DR Ensembl; ENST00000264938; ENSP00000264938; ENSG00000066230.
DR GeneID; 6550; -.
DR KEGG; hsa:6550; -.
DR UCSC; uc003jbe.2; human.
DR CTD; 6550; -.
DR GeneCards; GC05M000473; -.
DR H-InvDB; HIX0004707; -.
DR H-InvDB; HIX0032039; -.
DR HGNC; HGNC:11073; SLC9A3.
DR HPA; HPA036493; -.
DR HPA; HPA036669; -.
DR MIM; 182307; gene.
DR neXtProt; NX_P48764; -.
DR PharmGKB; PA316; -.
DR eggNOG; COG0025; -.
DR HOGENOM; HOG000247044; -.
DR HOVERGEN; HBG052615; -.
DR InParanoid; P48764; -.
DR KO; K12040; -.
DR OMA; RDKWSNF; -.
DR OrthoDB; EOG7KQ20Z; -.
DR PhylomeDB; P48764; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR GeneWiki; Sodium%E2%80%93hydrogen_antiporter_3; -.
DR GenomeRNAi; 6550; -.
DR NextBio; 25493; -.
DR PRO; PR:P48764; -.
DR ArrayExpress; P48764; -.
DR Bgee; P48764; -.
DR CleanEx; HS_SLC9A3; -.
DR Genevestigator; P48764; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031526; C:brush border membrane; ISS:UniProtKB.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0030165; F:PDZ domain binding; ISS:UniProtKB.
DR GO; GO:0015385; F:sodium:hydrogen antiporter activity; ISS:UniProtKB.
DR GO; GO:0006885; P:regulation of pH; IEA:Ensembl.
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 Antiport; Cell membrane; Complete proteome; Glycoprotein;
KW Ion transport; Membrane; Phosphoprotein; Polymorphism;
KW Reference proteome; Sodium; Sodium transport; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1 834 Sodium/hydrogen exchanger 3.
FT /FTId=PRO_0000052356.
FT TOPO_DOM 1 12 Cytoplasmic (Potential).
FT INTRAMEM 13 24 Name=A/M1; (Potential).
FT TOPO_DOM 25 54 Cytoplasmic (Potential).
FT INTRAMEM 55 73 Name=B/M2; (Potential).
FT TOPO_DOM 74 79 Cytoplasmic (Potential).
FT TRANSMEM 80 99 Helical; Name=C/M3; (Potential).
FT TOPO_DOM 100 112 Extracellular (Potential).
FT TRANSMEM 113 133 Helical; Name=D/M4; (Potential).
FT TOPO_DOM 134 139 Cytoplasmic (Potential).
FT TRANSMEM 140 160 Helical; Name=E/M5; (Potential).
FT TOPO_DOM 161 180 Extracellular (Potential).
FT TRANSMEM 181 202 Helical; Name=F/M5A; (Potential).
FT TOPO_DOM 203 210 Cytoplasmic (Potential).
FT TRANSMEM 211 232 Helical; Name=G/M5B; (Potential).
FT TOPO_DOM 233 252 Extracellular (Potential).
FT TRANSMEM 253 274 Helical; Name=H/M6; (Potential).
FT TOPO_DOM 275 290 Cytoplasmic (Potential).
FT TRANSMEM 291 309 Helical; Name=I/M7; (Potential).
FT TOPO_DOM 310 340 Extracellular (Potential).
FT TRANSMEM 341 362 Helical; Name=J/M8; (Potential).
FT TOPO_DOM 363 369 Cytoplasmic (Potential).
FT TRANSMEM 370 390 Helical; Name=K/M9; (Potential).
FT TOPO_DOM 391 405 Extracellular (Potential).
FT INTRAMEM 406 426 Name=L; (Potential).
FT TOPO_DOM 427 435 Extracellular (Potential).
FT TRANSMEM 436 456 Helical; Name=M/M10; (Potential).
FT TOPO_DOM 457 834 Cytoplasmic (Potential).
FT REGION 590 667 Interaction with PDZD3 (By similarity).
FT MOD_RES 555 555 Phosphoserine (By similarity).
FT MOD_RES 607 607 Phosphoserine (By similarity).
FT MOD_RES 663 663 Phosphoserine; by SGK1.
FT CARBOHYD 241 241 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 326 326 N-linked (GlcNAc...) (Potential).
FT VARIANT 799 799 C -> R (in dbSNP:rs2247114).
FT /FTId=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
//
MIM
182307
*RECORD*
*FIELD* NO
182307
*FIELD* TI
*182307 SOLUTE CARRIER FAMILY 9, MEMBER 3; SLC9A3
;;SODIUM/HYDROGEN EXCHANGER 3; NHE3;;
read moreSODIUM/HYDROGEN EXCHANGER, APICAL EPITHELIAL
*FIELD* TX
CLONING
An apical membrane Na+/H+ exchanger is involved in transepithelial,
electroneutral Na+ absorption across renal and intestinal epithelia. The
apical Na+/H+ exchange activity is pharmacologically distinct from the
basolateral Na+/H+ exchange activity, notably in terms of response to
kinase regulation and in addition by the diuretic amiloride. NHE1
(SLC9A1; 107310), the first of these exchangers to be cloned, localizes
by immunocytochemical studies only to the basolateral membranes of
polarized epithelial cells. In the course of cloning rabbit NHE3, Tse et
al. (1992) isolated from a human kidney cortex library a partial cDNA
that encodes a human NHE3 homolog.
MAPPING
By human/rodent somatic cell hybrid mapping panels, Brant et al. (1993)
mapped the SLC9A3 gene to chromosome 5p15.3.
Szpirer et al. (1994) concluded that there are 2 NHE3 genes in the human
and designated them NHE3A and NHE3B. The NHE3A and NHE3B genes were
assigned to chromosomes 10 and 5, respectively. Determination of which
chromosome contains the functional NHE3 gene and whether the other one
is a closely related gene or a pseudogene remained to be determined.
Kokke et al. (1996) concluded that the gene on chromosome 10 is a
pseudogene.
GENE FUNCTION
In a kidney proximal epithelial cell line (OKP) incubated in acid media,
Li et al. (2004) observed an increase in PYK2 phosphorylation and
PYK2/SRC binding. Transfection of OKP cells with dominant-negative PYK2
or small interfering PYK2 duplex RNA blocked acid activation of NHE3,
whereas neither had an effect on glucocorticoid activation of NHE3.
Dominant-negative PYK2 also blocked acid activation of SRC kinase
(190090), which is required for acid regulation of NHE3. Li et al.
(2004) concluded that PYK2 is directly activated by acidic pH and that
PYK2 activation is required for acid activation of SRC kinase and NHE3.
Partially purified PYK2 was activated by acid in a cell-free system,
leading Li et al. (2004) to suggest that PYK2 may serve as the pH sensor
that initiates the acid-regulated signaling cascade involved in NHE3
regulation.
Weinman et al. (2003) found that Nhe3 was expressed and targeted
correctly in brush border membranes prepared from sodium/hydrogen
exchanger regulatory factor-1 (NHERF1, or SLC9A3R1; 604990) -/- renal
proximal tubules and that basal Na+/H+ exchange was indistinguishable
from wildtype. However, Nherf1 -/- membranes were defective in PKA (see
601639)-mediated cAMP-dependent phosphorylation and inhibition of Nhe3
transport activity.
Using isolated wildtype and Nherf1 -/- mouse kidney cortex and ileum,
Murtazina et al. (2007) found that Nherf1 was required for all cAMP
inhibition of Nhe3 in kidney, which occurred through both Epac (RAPGEF3;
606057)-dependent and PKA-dependent mechanisms. In contrast, cAMP
inhibition of Nhe3 in ileum occurred only by a PKA-dependent pathway
that was independent of Nherf1.
MOLECULAR GENETICS
By Southern analysis of EcoRI-digested human genomic DNAs from CEPH
pedigrees, Brant et al. (1993) detected 3 polymorphic sites containing 9
alleles that segregate in a mendelian fashion. The observed
heterozygosity for the NHE3 locus in unrelated individuals was 71%.
Linkage analysis between NHE3 and other markers known to map at
chromosome 5p15 confirmed the localization of NHE3 to 5p15.3, making
NHE3 the most telomeric gene identified on 5p at that time.
ANIMAL MODEL
As the distribution of NHE3 overlaps with that of the NHE2 (SLC9A2;
600530) isoform in kidney and in intestine, the function and relative
importance of NHE3 in vivo required elucidation. To this end, Schultheis
et al. (1998) generated mice lacking NHE3 function. Homozygous mutant
mice survived but had slight diarrhea, and blood analysis revealed that
they were mildly acidotic. Bicarbonate and fluid absorption were sharply
reduced in proximal convoluted tubules, blood pressure was reduced, and
there was a severe absorptive defect in the intestine. Thus,
compensatory mechanisms must limit gross perturbations of electrolyte
and acid-base balance. Plasma aldosterone was increased in
NHE3-deficient mice, and expression of both renin and the AE1 (SLC4A1;
109270) chloride/bicarbonate exchanger mRNAs were induced in kidney. In
the colon, epithelial Na(+) channel activity was increased and colonic
H(+),K(+)-ATPase mRNA was massively induced. The data showed that NHE3
is the major absorptive Na(+)/H(+) exchanger in kidney and intestine,
and that lack of the exchanger impairs acid-base balance and Na(+)-fluid
volume homeostasis.
*FIELD* RF
1. Brant, S. R.; Bernstein, M.; Wasmuth, J. J.; Taylor, E. W.; McPherson,
J. D.; Li, X.; Walker, S.; Pouyssegur, J.; Donowitz, M.; Tse, C.-M.;
Jabs, E. W.: Physical and genetic mapping of a human apical epithelial
Na+/H+ exchanger (NHE3) isoform to chromosome 5p15.3. Genomics 15:
668-672, 1993.
2. Kokke, F. T. M.; Elsawy, T.; Bengtsson, U.; Wasmuth, J. J.; Jabs,
E. W.; Tse, C.-M.; Donowitz, M.; Brant, S. R.: A NHE3-related pseudogene
is on human chromosome 10; the functional gene maps to 5p15.3. Mammalian
Genome 7: 235-236, 1996.
3. Li, S.; Sato, S.; Yang, X.; Preisig, P. A.; Alpern, R. J.: Pyk2
activation is integral to acid stimulation of sodium/hydrogen exchanger
3. J. Clin. Invest. 114: 1782-1789, 2004.
4. Murtazina, R.; Kovbasnjuk, O.; Zachos, N. C.; Li, X.; Chen, Y.;
Hubbard, A.; Hogema, B. M.; Steplock, D.; Seidler, U.; Hoque, K. M.;
Tse, C. M.; De Jonge, H. R.; Weinman, E. J.; Donowitz, M.: Tissue-specific
regulation of sodium/proton exchanger isoform 3 activity in Na(+)/H(+)
exchanger regulatory factor 1 (NHERF1) null mice: cAMP inhibition
is differentially dependent on NHERF1 and exchange protein directly
activated by cAMP in ileum versus proximal tubule. J. Biol. Chem. 282:
25141-25151, 2007.
5. Schultheis, P. J.; Clarke, L. L.; Meneton, P.; Miller, M. L.; Soleimani,
M.; Gawenis, L. R.; Riddle, T. M.; Duffy, J. J.; Doetschman, T.; Wang,
T.; Giebisch, G.; Aronson, P. S.; Lorenz, J. N.; Shull, G. E.: Renal
and intestinal absorptive defects in mice lacking the NHE3 Na(+)/H(+)
exchanger. Nature Genet. 19: 282-285, 1998.
6. Szpirer, C.; Szpirer, J.; Riviere, M.; Levan, G.; Orlowski, J.
: Chromosomal assignment of four genes encoding Na/H exchanger isoforms
in human and rat. Mammalian Genome 5: 153-159, 1994.
7. Tse, C. M.; Brant, S. R.; Walker, S.; Pouyssegur, J.; Donowitz,
M.: Cloning and sequencing of a rabbit cDNA encoding an intestinal
and kidney-specific Na+/H+ exchanger isoform (NHE-3). J. Biol. Chem. 267:
9340-9346, 1992.
8. Weinman, E. J.; Steplock, D.; Shenolikar, S.: NHERF-1 uniquely
transduces the cAMP signals that inhibit sodium-hydrogen exchange
in mouse renal apical membranes. FEBS Lett. 536: 141-144, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 06/04/2012
Marla J. F. O'Neill - updated: 1/14/2005
Victor A. McKusick - updated: 6/24/1998
*FIELD* CD
Victor A. McKusick: 3/19/1993
*FIELD* ED
mgross: 06/04/2012
wwang: 4/21/2009
carol: 1/19/2005
terry: 1/14/2005
alopez: 6/29/1998
terry: 6/24/1998
terry: 1/17/1997
mark: 4/28/1996
terry: 4/24/1996
mark: 5/15/1995
carol: 4/30/1993
carol: 3/19/1993
*RECORD*
*FIELD* NO
182307
*FIELD* TI
*182307 SOLUTE CARRIER FAMILY 9, MEMBER 3; SLC9A3
;;SODIUM/HYDROGEN EXCHANGER 3; NHE3;;
read moreSODIUM/HYDROGEN EXCHANGER, APICAL EPITHELIAL
*FIELD* TX
CLONING
An apical membrane Na+/H+ exchanger is involved in transepithelial,
electroneutral Na+ absorption across renal and intestinal epithelia. The
apical Na+/H+ exchange activity is pharmacologically distinct from the
basolateral Na+/H+ exchange activity, notably in terms of response to
kinase regulation and in addition by the diuretic amiloride. NHE1
(SLC9A1; 107310), the first of these exchangers to be cloned, localizes
by immunocytochemical studies only to the basolateral membranes of
polarized epithelial cells. In the course of cloning rabbit NHE3, Tse et
al. (1992) isolated from a human kidney cortex library a partial cDNA
that encodes a human NHE3 homolog.
MAPPING
By human/rodent somatic cell hybrid mapping panels, Brant et al. (1993)
mapped the SLC9A3 gene to chromosome 5p15.3.
Szpirer et al. (1994) concluded that there are 2 NHE3 genes in the human
and designated them NHE3A and NHE3B. The NHE3A and NHE3B genes were
assigned to chromosomes 10 and 5, respectively. Determination of which
chromosome contains the functional NHE3 gene and whether the other one
is a closely related gene or a pseudogene remained to be determined.
Kokke et al. (1996) concluded that the gene on chromosome 10 is a
pseudogene.
GENE FUNCTION
In a kidney proximal epithelial cell line (OKP) incubated in acid media,
Li et al. (2004) observed an increase in PYK2 phosphorylation and
PYK2/SRC binding. Transfection of OKP cells with dominant-negative PYK2
or small interfering PYK2 duplex RNA blocked acid activation of NHE3,
whereas neither had an effect on glucocorticoid activation of NHE3.
Dominant-negative PYK2 also blocked acid activation of SRC kinase
(190090), which is required for acid regulation of NHE3. Li et al.
(2004) concluded that PYK2 is directly activated by acidic pH and that
PYK2 activation is required for acid activation of SRC kinase and NHE3.
Partially purified PYK2 was activated by acid in a cell-free system,
leading Li et al. (2004) to suggest that PYK2 may serve as the pH sensor
that initiates the acid-regulated signaling cascade involved in NHE3
regulation.
Weinman et al. (2003) found that Nhe3 was expressed and targeted
correctly in brush border membranes prepared from sodium/hydrogen
exchanger regulatory factor-1 (NHERF1, or SLC9A3R1; 604990) -/- renal
proximal tubules and that basal Na+/H+ exchange was indistinguishable
from wildtype. However, Nherf1 -/- membranes were defective in PKA (see
601639)-mediated cAMP-dependent phosphorylation and inhibition of Nhe3
transport activity.
Using isolated wildtype and Nherf1 -/- mouse kidney cortex and ileum,
Murtazina et al. (2007) found that Nherf1 was required for all cAMP
inhibition of Nhe3 in kidney, which occurred through both Epac (RAPGEF3;
606057)-dependent and PKA-dependent mechanisms. In contrast, cAMP
inhibition of Nhe3 in ileum occurred only by a PKA-dependent pathway
that was independent of Nherf1.
MOLECULAR GENETICS
By Southern analysis of EcoRI-digested human genomic DNAs from CEPH
pedigrees, Brant et al. (1993) detected 3 polymorphic sites containing 9
alleles that segregate in a mendelian fashion. The observed
heterozygosity for the NHE3 locus in unrelated individuals was 71%.
Linkage analysis between NHE3 and other markers known to map at
chromosome 5p15 confirmed the localization of NHE3 to 5p15.3, making
NHE3 the most telomeric gene identified on 5p at that time.
ANIMAL MODEL
As the distribution of NHE3 overlaps with that of the NHE2 (SLC9A2;
600530) isoform in kidney and in intestine, the function and relative
importance of NHE3 in vivo required elucidation. To this end, Schultheis
et al. (1998) generated mice lacking NHE3 function. Homozygous mutant
mice survived but had slight diarrhea, and blood analysis revealed that
they were mildly acidotic. Bicarbonate and fluid absorption were sharply
reduced in proximal convoluted tubules, blood pressure was reduced, and
there was a severe absorptive defect in the intestine. Thus,
compensatory mechanisms must limit gross perturbations of electrolyte
and acid-base balance. Plasma aldosterone was increased in
NHE3-deficient mice, and expression of both renin and the AE1 (SLC4A1;
109270) chloride/bicarbonate exchanger mRNAs were induced in kidney. In
the colon, epithelial Na(+) channel activity was increased and colonic
H(+),K(+)-ATPase mRNA was massively induced. The data showed that NHE3
is the major absorptive Na(+)/H(+) exchanger in kidney and intestine,
and that lack of the exchanger impairs acid-base balance and Na(+)-fluid
volume homeostasis.
*FIELD* RF
1. Brant, S. R.; Bernstein, M.; Wasmuth, J. J.; Taylor, E. W.; McPherson,
J. D.; Li, X.; Walker, S.; Pouyssegur, J.; Donowitz, M.; Tse, C.-M.;
Jabs, E. W.: Physical and genetic mapping of a human apical epithelial
Na+/H+ exchanger (NHE3) isoform to chromosome 5p15.3. Genomics 15:
668-672, 1993.
2. Kokke, F. T. M.; Elsawy, T.; Bengtsson, U.; Wasmuth, J. J.; Jabs,
E. W.; Tse, C.-M.; Donowitz, M.; Brant, S. R.: A NHE3-related pseudogene
is on human chromosome 10; the functional gene maps to 5p15.3. Mammalian
Genome 7: 235-236, 1996.
3. Li, S.; Sato, S.; Yang, X.; Preisig, P. A.; Alpern, R. J.: Pyk2
activation is integral to acid stimulation of sodium/hydrogen exchanger
3. J. Clin. Invest. 114: 1782-1789, 2004.
4. Murtazina, R.; Kovbasnjuk, O.; Zachos, N. C.; Li, X.; Chen, Y.;
Hubbard, A.; Hogema, B. M.; Steplock, D.; Seidler, U.; Hoque, K. M.;
Tse, C. M.; De Jonge, H. R.; Weinman, E. J.; Donowitz, M.: Tissue-specific
regulation of sodium/proton exchanger isoform 3 activity in Na(+)/H(+)
exchanger regulatory factor 1 (NHERF1) null mice: cAMP inhibition
is differentially dependent on NHERF1 and exchange protein directly
activated by cAMP in ileum versus proximal tubule. J. Biol. Chem. 282:
25141-25151, 2007.
5. Schultheis, P. J.; Clarke, L. L.; Meneton, P.; Miller, M. L.; Soleimani,
M.; Gawenis, L. R.; Riddle, T. M.; Duffy, J. J.; Doetschman, T.; Wang,
T.; Giebisch, G.; Aronson, P. S.; Lorenz, J. N.; Shull, G. E.: Renal
and intestinal absorptive defects in mice lacking the NHE3 Na(+)/H(+)
exchanger. Nature Genet. 19: 282-285, 1998.
6. Szpirer, C.; Szpirer, J.; Riviere, M.; Levan, G.; Orlowski, J.
: Chromosomal assignment of four genes encoding Na/H exchanger isoforms
in human and rat. Mammalian Genome 5: 153-159, 1994.
7. Tse, C. M.; Brant, S. R.; Walker, S.; Pouyssegur, J.; Donowitz,
M.: Cloning and sequencing of a rabbit cDNA encoding an intestinal
and kidney-specific Na+/H+ exchanger isoform (NHE-3). J. Biol. Chem. 267:
9340-9346, 1992.
8. Weinman, E. J.; Steplock, D.; Shenolikar, S.: NHERF-1 uniquely
transduces the cAMP signals that inhibit sodium-hydrogen exchange
in mouse renal apical membranes. FEBS Lett. 536: 141-144, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 06/04/2012
Marla J. F. O'Neill - updated: 1/14/2005
Victor A. McKusick - updated: 6/24/1998
*FIELD* CD
Victor A. McKusick: 3/19/1993
*FIELD* ED
mgross: 06/04/2012
wwang: 4/21/2009
carol: 1/19/2005
terry: 1/14/2005
alopez: 6/29/1998
terry: 6/24/1998
terry: 1/17/1997
mark: 4/28/1996
terry: 4/24/1996
mark: 5/15/1995
carol: 4/30/1993
carol: 3/19/1993