ID   VGLU2_HUMAN             Reviewed;         582 AA.
AC   Q9P2U8; A6NKS2;
DT   05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-2000, sequence version 1.
DT   24-JAN-2024, entry version 163.
DE   RecName: Full=Vesicular glutamate transporter 2 {ECO:0000303|PubMed:11698620};
DE            Short=VGluT2 {ECO:0000303|PubMed:11698620};
DE   AltName: Full=Differentiation-associated BNPI {ECO:0000303|PubMed:11698620};
DE   AltName: Full=Differentiation-associated Na(+)-dependent inorganic phosphate cotransporter {ECO:0000303|PubMed:10820226};
DE   AltName: Full=Solute carrier family 17 member 6;
GN   Name=SLC17A6 {ECO:0000312|HGNC:HGNC:16703};
GN   Synonyms=DNPI {ECO:0000303|PubMed:10820226}, VGLUT2
GN   {ECO:0000303|PubMed:11698620};
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 [MRNA], FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL
RP   STAGE.
RC   TISSUE=Thalamus;
RX   PubMed=10820226; DOI=10.1046/j.1471-4159.2000.0742622.x;
RA   Aihara Y., Mashima H., Onda H., Hisano S., Kasuya H., Hori T., Yamada S.,
RA   Tomura H., Yamada Y., Inoue I., Kojima I., Takeda J.;
RT   "Molecular cloning of a novel brain-type Na(+)-dependent inorganic
RT   phosphate cotransporter.";
RL   J. Neurochem. 74:2622-2625(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16554811; DOI=10.1038/nature04632;
RA   Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA   Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA   Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA   Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA   Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA   Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT   "Human chromosome 11 DNA sequence and analysis including novel gene
RT   identification.";
RL   Nature 440:497-500(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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   [5]
RP   FUNCTION, TRANSPORTER ACTIVITY, AND SUBCELLULAR LOCATION.
RX   PubMed=11698620; DOI=10.1523/jneurosci.21-22-j0002.2001;
RA   Takamori S., Rhee J.S., Rosenmund C., Jahn R.;
RT   "Identification of differentiation-associated brain-specific phosphate
RT   transporter as a second vesicular glutamate transporter (VGLUT2).";
RL   J. Neurosci. 21:RC182-RC182(2001).
RN   [6]
RP   FUNCTION, TRANSPORTER ACTIVITY, AND SUBCELLULAR LOCATION.
RX   PubMed=33440152; DOI=10.1016/j.celrep.2020.108623;
RA   Cheret C., Ganzella M., Preobraschenski J., Jahn R., Ahnert-Hilger G.;
RT   "Vesicular Glutamate Transporters (SLCA17 A6, 7, 8) Control Synaptic
RT   Phosphate Levels.";
RL   Cell Rep. 34:108623-108623(2021).
RN   [7]
RP   VARIANT [LARGE SCALE ANALYSIS] SER-40.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA   Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA   Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA   Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA   Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal cancers.";
RL   Science 314:268-274(2006).
CC   -!- FUNCTION: Multifunctional transporter that transports L-glutamate as
CC       well as multiple ions such as chloride, proton, potassium, sodium and
CC       phosphate (PubMed:33440152, PubMed:11698620). At the synaptic vesicle
CC       membrane, mainly functions as a uniporter which transports
CC       preferentially L-glutamate but also, phosphate from the cytoplasm into
CC       synaptic vesicles at presynaptic nerve terminals of excitatory neural
CC       cells (PubMed:11698620). The L-glutamate or phosphate uniporter
CC       activity is electrogenic and is driven by the proton electrochemical
CC       gradient, mainly by the electrical gradient established by the vacuolar
CC       H(+)-ATPase across the synaptic vesicle membrane (PubMed:11698620). In
CC       addition, functions as a chloride channel that allows the chloride
CC       permeation through the synaptic vesicle membrane therefore affects the
CC       proton electrochemical gradient and promotes synaptic vesicles
CC       acidification (By similarity). Moreover, functions as a vesicular
CC       K(+)/H(+) antiport allowing to maintain the electrical gradient and to
CC       decrease chemical gradient and therefore sustain vesicular glutamate
CC       uptake (By similarity). The vesicular H(+)/H(+) antiport activity is
CC       electroneutral (By similarity). At the plasma membrane, following
CC       exocytosis, functions as a symporter of Na(+) and phosphate from the
CC       extracellular space to the cytoplasm allowing synaptic phosphate
CC       homeostasis regulation (Probable) (PubMed:10820226). The symporter
CC       activity is driven by an inside negative membrane potential and is
CC       electrogenic (Probable). Also involved in the regulation of retinal
CC       hyaloid vessel regression during postnatal development (By similarity).
CC       May also play a role in the endocrine glutamatergic system of other
CC       tissues such as pineal gland and pancreas (By similarity).
CC       {ECO:0000250|UniProtKB:Q8BLE7, ECO:0000250|UniProtKB:Q9JI12,
CC       ECO:0000269|PubMed:10820226, ECO:0000269|PubMed:11698620,
CC       ECO:0000305|PubMed:33440152}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-glutamate(out) = L-glutamate(in); Xref=Rhea:RHEA:66336,
CC         ChEBI:CHEBI:29985; Evidence={ECO:0000269|PubMed:11698620};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3 Na(+)(out) + phosphate(out) = 3 Na(+)(in) + phosphate(in);
CC         Xref=Rhea:RHEA:71255, ChEBI:CHEBI:29101, ChEBI:CHEBI:43474;
CC         Evidence={ECO:0000305|PubMed:33440152};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=phosphate(in) = phosphate(out); Xref=Rhea:RHEA:32823,
CC         ChEBI:CHEBI:43474; Evidence={ECO:0000250|UniProtKB:Q9JI12};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H(+)(out) + K(+)(in) = H(+)(in) + K(+)(out);
CC         Xref=Rhea:RHEA:29467, ChEBI:CHEBI:15378, ChEBI:CHEBI:29103;
CC         Evidence={ECO:0000250|UniProtKB:Q9JI12};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823,
CC         ChEBI:CHEBI:17996; Evidence={ECO:0000250|UniProtKB:Q9JI12};
CC   -!- ACTIVITY REGULATION: Chloride channel activity is allosterically
CC       activated by lumenal H(+) and Cl(-) leading to synaptic vesicles
CC       acidification. The L-glutamate transport activity is allosterically
CC       activated by lumenal H(+) and Cl(-). The allosteric requirement for
CC       H(+) efficiently prevents non-vesicular efflux across the plasma
CC       membrane. The L-glutamate uniporter activity exhibits a biphasic
CC       dependence on chloride concentration. {ECO:0000250|UniProtKB:Q9JI12}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle, synaptic
CC       vesicle membrane {ECO:0000269|PubMed:11698620}; Multi-pass membrane
CC       protein {ECO:0000255}. Synapse, synaptosome
CC       {ECO:0000250|UniProtKB:Q8BLE7}. Cell membrane
CC       {ECO:0000305|PubMed:33440152}; Multi-pass membrane protein
CC       {ECO:0000255}.
CC   -!- TISSUE SPECIFICITY: Predominantly expressed in adult brain
CC       (PubMed:10820226). Expressed in amygdala, caudate nucleus, cerebral
CC       cortex, frontal lobe, hippocampus, medulla, occipital lobe, putamen,
CC       spinal cord, substantia nigra, subthalamic nucleus, temporal lobe and
CC       thalamus (PubMed:10820226). {ECO:0000269|PubMed:10820226}.
CC   -!- DEVELOPMENTAL STAGE: Expressed in fetal brain.
CC       {ECO:0000269|PubMed:10820226}.
CC   -!- SIMILARITY: Belongs to the major facilitator superfamily. Sodium/anion
CC       cotransporter family. VGLUT subfamily. {ECO:0000305}.
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DR   EMBL; AB032435; BAA92874.1; -; mRNA.
DR   EMBL; AC040936; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471064; EAW68324.1; -; Genomic_DNA.
DR   EMBL; BC069629; AAH69629.1; -; mRNA.
DR   EMBL; BC069640; AAH69640.1; -; mRNA.
DR   EMBL; BC069646; AAH69646.1; -; mRNA.
DR   CCDS; CCDS7856.1; -.
DR   RefSeq; NP_065079.1; NM_020346.2.
DR   AlphaFoldDB; Q9P2U8; -.
DR   SMR; Q9P2U8; -.
DR   BioGRID; 121355; 1.
DR   IntAct; Q9P2U8; 1.
DR   STRING; 9606.ENSP00000263160; -.
DR   TCDB; 2.A.1.14.31; the major facilitator superfamily (mfs).
DR   GlyCosmos; Q9P2U8; 3 sites, No reported glycans.
DR   GlyGen; Q9P2U8; 3 sites.
DR   iPTMnet; Q9P2U8; -.
DR   PhosphoSitePlus; Q9P2U8; -.
DR   BioMuta; SLC17A6; -.
DR   DMDM; 74734915; -.
DR   MassIVE; Q9P2U8; -.
DR   PaxDb; 9606-ENSP00000263160; -.
DR   PeptideAtlas; Q9P2U8; -.
DR   ProteomicsDB; 83899; -.
DR   Antibodypedia; 25332; 267 antibodies from 31 providers.
DR   DNASU; 57084; -.
DR   Ensembl; ENST00000263160.4; ENSP00000263160.3; ENSG00000091664.9.
DR   GeneID; 57084; -.
DR   KEGG; hsa:57084; -.
DR   MANE-Select; ENST00000263160.4; ENSP00000263160.3; NM_020346.3; NP_065079.1.
DR   UCSC; uc001mqk.4; human.
DR   AGR; HGNC:16703; -.
DR   CTD; 57084; -.
DR   DisGeNET; 57084; -.
DR   GeneCards; SLC17A6; -.
DR   HGNC; HGNC:16703; SLC17A6.
DR   HPA; ENSG00000091664; Tissue enhanced (brain, pituitary gland, retina).
DR   MIM; 607563; gene.
DR   neXtProt; NX_Q9P2U8; -.
DR   OpenTargets; ENSG00000091664; -.
DR   PharmGKB; PA424; -.
DR   VEuPathDB; HostDB:ENSG00000091664; -.
DR   eggNOG; KOG2532; Eukaryota.
DR   GeneTree; ENSGT00940000155891; -.
DR   HOGENOM; CLU_001265_5_0_1; -.
DR   InParanoid; Q9P2U8; -.
DR   OMA; YNEQSQM; -.
DR   OrthoDB; 2685946at2759; -.
DR   PhylomeDB; Q9P2U8; -.
DR   TreeFam; TF313535; -.
DR   PathwayCommons; Q9P2U8; -.
DR   Reactome; R-HSA-428643; Organic anion transporters.
DR   BioGRID-ORCS; 57084; 7 hits in 1146 CRISPR screens.
DR   ChiTaRS; SLC17A6; human.
DR   GenomeRNAi; 57084; -.
DR   Pharos; Q9P2U8; Tbio.
DR   PRO; PR:Q9P2U8; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; Q9P2U8; Protein.
DR   Bgee; ENSG00000091664; Expressed in lateral nuclear group of thalamus and 52 other cell types or tissues.
DR   GO; GO:0034707; C:chloride channel complex; IEA:UniProtKB-KW.
DR   GO; GO:0060076; C:excitatory synapse; IBA:GO_Central.
DR   GO; GO:0043005; C:neuron projection; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0030672; C:synaptic vesicle membrane; IDA:UniProtKB.
DR   GO; GO:0005254; F:chloride channel activity; ISS:UniProtKB.
DR   GO; GO:0005313; F:L-glutamate transmembrane transporter activity; IBA:GO_Central.
DR   GO; GO:0140788; F:L-glutamate uniporter activity; IDA:UniProtKB.
DR   GO; GO:0005326; F:neurotransmitter transmembrane transporter activity; IBA:GO_Central.
DR   GO; GO:0015386; F:potassium:proton antiporter activity; ISS:UniProtKB.
DR   GO; GO:0005436; F:sodium:phosphate symporter activity; ISS:UniProtKB.
DR   GO; GO:1990384; P:hyaloid vascular plexus regression; ISS:UniProtKB.
DR   GO; GO:0051938; P:L-glutamate import; IMP:UniProtKB.
DR   GO; GO:0006820; P:monoatomic anion transport; IBA:GO_Central.
DR   GO; GO:0006811; P:monoatomic ion transport; TAS:Reactome.
DR   GO; GO:0098700; P:neurotransmitter loading into synaptic vesicle; IMP:SynGO.
DR   GO; GO:0055062; P:phosphate ion homeostasis; IDA:UniProtKB.
DR   GO; GO:0006817; P:phosphate ion transport; ISS:UniProtKB.
DR   GO; GO:0050803; P:regulation of synapse structure or activity; IBA:GO_Central.
DR   GO; GO:0044341; P:sodium-dependent phosphate transport; ISS:UniProtKB.
DR   GO; GO:0035249; P:synaptic transmission, glutamatergic; IBA:GO_Central.
DR   CDD; cd17382; MFS_SLC17A6_7_8_VGluT; 1.
DR   Gene3D; 1.20.1250.20; MFS general substrate transporter like domains; 2.
DR   InterPro; IPR011701; MFS.
DR   InterPro; IPR020846; MFS_dom.
DR   InterPro; IPR036259; MFS_trans_sf.
DR   PANTHER; PTHR11662; SOLUTE CARRIER FAMILY 17; 1.
DR   PANTHER; PTHR11662:SF201; VESICULAR GLUTAMATE TRANSPORTER 2; 1.
DR   Pfam; PF07690; MFS_1; 1.
DR   SUPFAM; SSF103473; MFS general substrate transporter; 1.
DR   PROSITE; PS50850; MFS; 1.
DR   Genevisible; Q9P2U8; HS.
PE   2: Evidence at transcript level;
KW   Antiport; Cell membrane; Chloride; Chloride channel; Cytoplasmic vesicle;
KW   Glycoprotein; Ion channel; Ion transport; Membrane;
KW   Neurotransmitter transport; Phosphate transport; Reference proteome;
KW   Sodium; Sodium transport; Symport; Synapse; Synaptosome; Transmembrane;
KW   Transmembrane helix; Transport.
FT   CHAIN           1..582
FT                   /note="Vesicular glutamate transporter 2"
FT                   /id="PRO_0000318169"
FT   TOPO_DOM        1..71
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        72..92
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        93..125
FT                   /note="Vesicular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        126..146
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        147..148
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        149..169
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        170..177
FT                   /note="Vesicular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        178..198
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        199..216
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        217..237
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        238..244
FT                   /note="Vesicular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        245..265
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        266..310
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        311..331
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        332..349
FT                   /note="Vesicular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        350..370
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        371..386
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        387..407
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        408..409
FT                   /note="Vesicular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        410..430
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        431..443
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        444..464
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        465..477
FT                   /note="Vesicular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        478..498
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        499..582
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        100
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        101
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        470
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VARIANT         40
FT                   /note="T -> S (in a breast cancer sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:16959974"
FT                   /id="VAR_038710"
FT   VARIANT         551
FT                   /note="N -> S (in dbSNP:rs7117340)"
FT                   /id="VAR_038711"
SQ   SEQUENCE   582 AA;  64392 MW;  CE761E56FA18C6AD CRC64;
     MESVKQRILA PGKEGLKNFA GKSLGQIYRV LEKKQDTGET IELTEDGKPL EVPERKAPLC
     DCTCFGLPRR YIIAIMSGLG FCISFGIRCN LGVAIVDMVN NSTIHRGGKV IKEKAKFNWD
     PETVGMIHGS FFWGYIITQI PGGYIASRLA ANRVFGAAIL LTSTLNMLIP SAARVHYGCV
     IFVRILQGLV EGVTYPACHG IWSKWAPPLE RSRLATTSFC GSYAGAVIAM PLAGILVQYT
     GWSSVFYVYG SFGMVWYMFW LLVSYESPAK HPTITDEERR YIEESIGESA NLLGAMEKFK
     TPWRKFFTSM PVYAIIVANF CRSWTFYLLL ISQPAYFEEV FGFEISKVGM LSAVPHLVMT
     IIVPIGGQIA DFLRSKQILS TTTVRKIMNC GGFGMEATLL LVVGYSHTRG VAISFLVLAV
     GFSGFAISGF NVNHLDIAPR YASILMGISN GVGTLSGMVC PIIVGAMTKN KSREEWQYVF
     LIAALVHYGG VIFYAIFASG EKQPWADPEE TSEEKCGFIH EDELDEETGD ITQNYINYGT
     TKSYGATTQA NGGWPSGWEK KEEFVQGEVQ DSHSYKDRVD YS
//