ID   SC5A3_HUMAN             Reviewed;         718 AA.
AC   P53794; O43489;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   24-JAN-2024, sequence version 4.
DT   27-MAR-2024, entry version 183.
DE   RecName: Full=Sodium/myo-inositol cotransporter {ECO:0000305};
DE            Short=Na(+)/myo-inositol cotransporter;
DE   AltName: Full=Sodium/myo-inositol transporter 1;
DE            Short=SMIT1;
DE   AltName: Full=Solute carrier family 5 member 3;
GN   Name=SLC5A3 {ECO:0000312|HGNC:HGNC:11038};
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 [GENOMIC DNA].
RC   TISSUE=Placenta;
RX   PubMed=7789985; DOI=10.1016/0888-7543(95)80052-n;
RA   Berry G.T., Mallee J.J., Kwon H.M., Rim J.S., Mulla W.R., Muenke M.,
RA   Spinner N.B.;
RT   "The human osmoregulatory Na+/myo-inositol cotransporter gene (SLC5A3):
RT   molecular cloning and localization to chromosome 21.";
RL   Genomics 25:507-513(1995).
RN   [2]
RP   SEQUENCE REVISION TO 50 AND 566.
RA   Berry G.T., Mallee J.J., Kwon H.M., Rim J.S., Mulla W.R., Muenke M.,
RA   Spinner N.B.;
RL   Submitted (APR-2004) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-50 AND GLN-566.
RX   PubMed=9441750; DOI=10.1006/geno.1997.5055;
RA   Mallee J.J., Atta M.G., Lorica V., Rim J.S., Kwon H.M., Lucente A.D.,
RA   Wang Y., Berry G.T.;
RT   "The structural organization of the human Na+/myo-inositol cotransporter
RT   (SLC5A3) gene and characterization of the promoter.";
RL   Genomics 46:459-465(1997).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=10830953; DOI=10.1038/35012518;
RA   Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S.,
RA   Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M.,
RA   Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U.,
RA   Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A.,
RA   Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J.,
RA   Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K.,
RA   Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G.,
RA   Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J.,
RA   Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S.,
RA   Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K.,
RA   Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.;
RT   "The DNA sequence of human chromosome 21.";
RL   Nature 405:311-319(2000).
RN   [5]
RP   INDUCTION.
RX   PubMed=21679696; DOI=10.1016/j.bbrc.2011.06.001;
RA   Kage-Nakadai E., Uehara T., Mitani S.;
RT   "H+/myo-inositol transporter genes, hmit-1.1 and hmit-1.2, have roles in
RT   the osmoprotective response in Caenorhabditis elegans.";
RL   Biochem. Biophys. Res. Commun. 410:471-477(2011).
RN   [6]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-594 AND SER-632, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [7]
RP   FUNCTION, TRANSPORT ACTIVITY, AND INTERACTION WITH KCNQ1.
RX   PubMed=24595108; DOI=10.1126/scisignal.2005025;
RA   Abbott G.W., Tai K.K., Neverisky D.L., Hansler A., Hu Z., Roepke T.K.,
RA   Lerner D.J., Chen Q., Liu L., Zupan B., Toth M., Haynes R., Huang X.,
RA   Demirbas D., Buccafusca R., Gross S.S., Kanda V.A., Berry G.T.;
RT   "KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally
RT   regulating complexes that affect neuronal excitability.";
RL   Sci. Signal. 7:ra22-ra22(2014).
RN   [8]
RP   FUNCTION, AND INDUCTION.
RX   PubMed=27217553; DOI=10.1073/pnas.1606348113;
RA   Dai G., Yu H., Kruse M., Traynor-Kaplan A., Hille B.;
RT   "Osmoregulatory inositol transporter SMIT1 modulates electrical activity by
RT   adjusting PI(4,5)P2 levels.";
RL   Proc. Natl. Acad. Sci. U.S.A. 113:E3290-E3299(2016).
RN   [9]
RP   FUNCTION, AND INTERACTION WITH KCNQ2.
RX   PubMed=28793216; DOI=10.1016/j.bpj.2017.06.055;
RA   Manville R.W., Neverisky D.L., Abbott G.W.;
RT   "SMIT1 Modifies KCNQ Channel Function and Pharmacology by Physical
RT   Interaction with the Pore.";
RL   Biophys. J. 113:613-626(2017).
CC   -!- FUNCTION: Electrogenic Na(+)-coupled sugar symporter that actively
CC       transports myo-inositol and its stereoisomer scyllo-inositol across the
CC       plasma membrane, with a Na(+) to sugar coupling ratio of 2:1 (By
CC       similarity). Maintains myo-inositol concentration gradient that defines
CC       cell volume and fluid balance during osmotic stress, in particular in
CC       the fetoplacental unit and central nervous system (By similarity).
CC       Forms coregulatory complexes with voltage-gated K(+) ion channels,
CC       allosterically altering ion selectivity, voltage dependence and gating
CC       kinetics of the channel. In turn, K(+) efflux through the channel forms
CC       a local electrical gradient that modulates electrogenic Na(+)-coupled
CC       myo-inositol influx through the transporter (PubMed:24595108,
CC       PubMed:28793216). Associates with KCNQ1-KCNE2 channel in the apical
CC       membrane of choroid plexus epithelium and regulates the myo-inositol
CC       gradient between blood and cerebrospinal fluid with an impact on neuron
CC       excitability (PubMed:24595108) (By similarity). Associates with KCNQ2-
CC       KCNQ3 channel altering ion selectivity, increasing Na(+) and Cs(+)
CC       permeation relative to K(+) permeation (PubMed:28793216). Provides myo-
CC       inositol precursor for biosynthesis of phosphoinositides such as
CC       PI(4,5)P2, thus indirectly affecting the activity of phosphoinositide-
CC       dependent ion channels and Ca(2+) signaling upon osmotic stress
CC       (PubMed:27217553). {ECO:0000250|UniProtKB:P31637,
CC       ECO:0000250|UniProtKB:Q9JKZ2, ECO:0000269|PubMed:24595108,
CC       ECO:0000269|PubMed:27217553, ECO:0000269|PubMed:28793216}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=myo-inositol(out) + 2 Na(+)(out) = myo-inositol(in) + 2
CC         Na(+)(in); Xref=Rhea:RHEA:72987, ChEBI:CHEBI:17268,
CC         ChEBI:CHEBI:29101; Evidence={ECO:0000250|UniProtKB:P31637,
CC         ECO:0000269|PubMed:24595108};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=2 Na(+)(out) + scyllo-inositol(out) = 2 Na(+)(in) + scyllo-
CC         inositol(in); Xref=Rhea:RHEA:72991, ChEBI:CHEBI:10642,
CC         ChEBI:CHEBI:29101; Evidence={ECO:0000250|UniProtKB:P31637};
CC   -!- SUBUNIT: Interacts with KCNQ2 (via the pore module) (PubMed:28793216).
CC       Interacts with KCNQ1; this interaction is direct (PubMed:24595108).
CC       Forms coregulatory complexes with ion channels KCNQ2-KCNQ3 and KCNQ1-
CC       KCNE2 (PubMed:24595108, PubMed:28793216). {ECO:0000269|PubMed:24595108,
CC       ECO:0000269|PubMed:28793216}.
CC   -!- SUBCELLULAR LOCATION: Apical cell membrane
CC       {ECO:0000250|UniProtKB:Q9JKZ2}; Multi-pass membrane protein
CC       {ECO:0000255}. Basolateral cell membrane
CC       {ECO:0000250|UniProtKB:Q9JKZ2}; Multi-pass membrane protein
CC       {ECO:0000255}. Note=Colocalizes with KCNQ1 at the apical membrane of
CC       choroid plexus epithelium. {ECO:0000250|UniProtKB:Q9JKZ2}.
CC   -!- INDUCTION: Induced by hyperosmotic stress.
CC       {ECO:0000269|PubMed:21679696, ECO:0000269|PubMed:27217553}.
CC   -!- SIMILARITY: Belongs to the sodium:solute symporter (SSF) (TC 2.A.21)
CC       family. {ECO:0000305}.
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DR   EMBL; L38500; AAC41747.2; -; Genomic_DNA.
DR   EMBL; AF027153; AAC39548.1; -; Genomic_DNA.
DR   EMBL; AP001719; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS33549.1; -.
DR   PIR; A56851; A56851.
DR   RefSeq; NP_008864.4; NM_006933.6.
DR   AlphaFoldDB; P53794; -.
DR   SMR; P53794; -.
DR   IntAct; P53794; 12.
DR   MINT; P53794; -.
DR   STRING; 9606.ENSP00000370543; -.
DR   DrugBank; DB13178; Inositol.
DR   TCDB; 2.A.21.3.14; the solute:sodium symporter (sss) family.
DR   GlyCosmos; P53794; 1 site, No reported glycans.
DR   GlyGen; P53794; 2 sites, 1 O-linked glycan (1 site).
DR   iPTMnet; P53794; -.
DR   PhosphoSitePlus; P53794; -.
DR   SwissPalm; P53794; -.
DR   BioMuta; SLC5A3; -.
DR   DMDM; 3334498; -.
DR   EPD; P53794; -.
DR   jPOST; P53794; -.
DR   MassIVE; P53794; -.
DR   MaxQB; P53794; -.
DR   PaxDb; 9606-ENSP00000370543; -.
DR   PeptideAtlas; P53794; -.
DR   ProteomicsDB; 56620; -.
DR   Pumba; P53794; -.
DR   Antibodypedia; 8029; 240 antibodies from 28 providers.
DR   DNASU; 6526; -.
DR   Ensembl; ENST00000381151.5; ENSP00000370543.3; ENSG00000198743.7.
DR   GeneID; 6526; -.
DR   MANE-Select; ENST00000381151.5; ENSP00000370543.3; NM_006933.7; NP_008864.4.
DR   UCSC; uc002yto.4; human.
DR   AGR; HGNC:11038; -.
DR   GeneCards; SLC5A3; -.
DR   HGNC; HGNC:11038; SLC5A3.
DR   HPA; ENSG00000198743; Tissue enhanced (kidney, thyroid gland).
DR   MIM; 600444; gene.
DR   neXtProt; NX_P53794; -.
DR   OpenTargets; ENSG00000198743; -.
DR   PharmGKB; PA35903; -.
DR   VEuPathDB; HostDB:ENSG00000198743; -.
DR   eggNOG; KOG2349; Eukaryota.
DR   GeneTree; ENSGT00940000161679; -.
DR   HOGENOM; CLU_018808_9_2_1; -.
DR   InParanoid; P53794; -.
DR   PhylomeDB; P53794; -.
DR   TreeFam; TF352855; -.
DR   PathwayCommons; P53794; -.
DR   Reactome; R-HSA-429593; Inositol transporters.
DR   SignaLink; P53794; -.
DR   Pharos; P53794; Tbio.
DR   PRO; PR:P53794; -.
DR   Proteomes; UP000005640; Chromosome 21.
DR   RNAct; P53794; Protein.
DR   Bgee; ENSG00000198743; Expressed in renal medulla and 210 other cell types or 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:0016020; C:membrane; TAS:ProtInc.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:ARUK-UCL.
DR   GO; GO:0005886; C:plasma membrane; IDA:ARUK-UCL.
DR   GO; GO:0008076; C:voltage-gated potassium channel complex; IEA:Ensembl.
DR   GO; GO:0015150; F:fucose transmembrane transporter activity; ISS:ARUK-UCL.
DR   GO; GO:0005412; F:glucose:sodium symporter activity; ISS:ARUK-UCL.
DR   GO; GO:0005365; F:myo-inositol transmembrane transporter activity; ISS:ARUK-UCL.
DR   GO; GO:0005367; F:myo-inositol:sodium symporter activity; IDA:UniProtKB.
DR   GO; GO:0015146; F:pentose transmembrane transporter activity; ISS:ARUK-UCL.
DR   GO; GO:0015166; F:polyol transmembrane transporter activity; ISS:ARUK-UCL.
DR   GO; GO:0015459; F:potassium channel regulator activity; IDA:ARUK-UCL.
DR   GO; GO:0044325; F:transmembrane transporter binding; IPI:ARUK-UCL.
DR   GO; GO:0015756; P:fucose transmembrane transport; ISS:ARUK-UCL.
DR   GO; GO:1904659; P:glucose transmembrane transport; ISS:ARUK-UCL.
DR   GO; GO:0006020; P:inositol metabolic process; IBA:GO_Central.
DR   GO; GO:1904679; P:myo-inositol import across plasma membrane; ISS:ARUK-UCL.
DR   GO; GO:0015798; P:myo-inositol transport; ISS:ARUK-UCL.
DR   GO; GO:0015750; P:pentose transmembrane transport; ISS:ARUK-UCL.
DR   GO; GO:0007422; P:peripheral nervous system development; IEA:Ensembl.
DR   GO; GO:0015791; P:polyol transmembrane transport; ISS:ARUK-UCL.
DR   GO; GO:0043085; P:positive regulation of catalytic activity; ISS:ARUK-UCL.
DR   GO; GO:1905477; P:positive regulation of protein localization to membrane; ISS:ARUK-UCL.
DR   GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; ISS:ARUK-UCL.
DR   GO; GO:0043576; P:regulation of respiratory gaseous exchange; IEA:Ensembl.
DR   GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL.
DR   CDD; cd11491; SLC5sbd_SMIT; 1.
DR   Gene3D; 1.20.1730.10; Sodium/glucose cotransporter; 1.
DR   InterPro; IPR038377; Na/Glc_symporter_sf.
DR   InterPro; IPR001734; Na/solute_symporter.
DR   InterPro; IPR018212; Na/solute_symporter_CS.
DR   InterPro; IPR042731; SMIT.
DR   NCBIfam; TIGR00813; sss; 1.
DR   PANTHER; PTHR11819:SF150; SODIUM_MYO-INOSITOL COTRANSPORTER; 1.
DR   PANTHER; PTHR11819; SOLUTE CARRIER FAMILY 5; 1.
DR   Pfam; PF00474; SSF; 1.
DR   PROSITE; PS00456; NA_SOLUT_SYMP_1; 1.
DR   PROSITE; PS00457; NA_SOLUT_SYMP_2; 1.
DR   PROSITE; PS50283; NA_SOLUT_SYMP_3; 1.
DR   Genevisible; P53794; HS.
PE   1: Evidence at protein level;
KW   Cell membrane; Glycoprotein; Ion transport; Membrane; Phosphoprotein;
KW   Reference proteome; Sodium; Sodium transport; Symport; Transmembrane;
KW   Transmembrane helix; Transport.
FT   CHAIN           1..718
FT                   /note="Sodium/myo-inositol cotransporter"
FT                   /id="PRO_0000105381"
FT   TOPO_DOM        1..9
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        10..29
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        30..38
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        39..57
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        58..86
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        87..110
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        111..123
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        124..144
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        145..157
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        158..183
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        184..186
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        187..205
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        206..303
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        304..324
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        325..353
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        354..376
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        377..406
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        407..430
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        431..443
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        444..462
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        463..510
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        511..532
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        533..695
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        696..716
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        717..718
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   SITE            24
FT                   /note="Implicated in sodium coupling"
FT                   /evidence="ECO:0000250"
FT   SITE            285
FT                   /note="Implicated in sodium coupling"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         594
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         632
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   CARBOHYD        232
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VARIANT         50
FT                   /note="A -> T (in dbSNP:rs8129891)"
FT                   /evidence="ECO:0000269|PubMed:9441750"
FT                   /id="VAR_061875"
FT   VARIANT         566
FT                   /note="K -> Q (in dbSNP:rs4817617)"
FT                   /evidence="ECO:0000269|PubMed:9441750"
FT                   /id="VAR_061876"
FT   CONFLICT        31
FT                   /note="S -> C (in Ref. 1; AAC41747)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   718 AA;  79664 MW;  E83EFF81DBF567BB CRC64;
     MRAVLDTADI AIVALYFILV MCIGFFAMWK SNRSTVSGYF LAGRSMTWVA IGASLFVSNI
     GSEHFIGLAG SGAASGFAVG AWEFNALLLL QLLGWVFIPI YIRSGVYTMP EYLSKRFGGH
     RIQVYFAALS LILYIFTKLS VDLYSGALFI QESLGWNLYV SVILLIGMTA LLTVTGGLVA
     VIYTDTLQAL LMIIGALTLM IISIMEIGGF EEVKRRYMLA SPDVTSILLT YNLSNTNSCN
     VSPKKEALKM LRNPTDEDVP WPGFILGQTP ASVWYWCADQ VIVQRVLAAK NIAHAKGSTL
     MAGFLKLLPM FIIVVPGMIS RILFTDDIAC INPEHCMLVC GSRAGCSNIA YPRLVMKLVP
     VGLRGLMMAV MIAALMSDLD SIFNSASTIF TLDVYKLIRK SASSRELMIV GRIFVAFMVV
     ISIAWVPIIV EMQGGQMYLY IQEVADYLTP PVAALFLLAI FWKRCNEQGA FYGGMAGFVL
     GAVRLILAFA YRAPECDQPD NRPGFIKDIH YMYVATGLFW VTGLITVIVS LLTPPPTKEQ
     IRTTTFWSKK NLVVKENCSP KEEPYKMQEK SILRCSENNE TINHIIPNGK SEDSIKGLQP
     EDVNLLVTCR EEGNPVASLG HSEAETPVDA YSNGQAALMG EKERKKETDD GGRYWKFIDW
     FCGFKSKSLS KRSLRDLMEE EAVCLQMLEE TRQVKVILNI GLFAVCSLGI FMFVYFSL
//