ID VGLU3_HUMAN Reviewed; 589 AA. AC Q8NDX2; B3KXZ6; B7ZKV4; Q17RQ8; DT 29-APR-2008, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2002, sequence version 1. DT 24-JAN-2024, entry version 167. DE RecName: Full=Vesicular glutamate transporter 3 {ECO:0000303|PubMed:12151341}; DE Short=VGluT3 {ECO:0000303|PubMed:12151341}; DE AltName: Full=Solute carrier family 17 member 8; GN Name=SLC17A8 {ECO:0000312|HGNC:HGNC:20151}; Synonyms=VGLUT3; 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] (ISOFORM 1), FUNCTION, TRANSPORTER ACTIVITY, AND RP TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=12151341; DOI=10.1093/embo-reports/kvf159; RA Takamori S., Malherbe P., Broger C., Jahn R.; RT "Molecular cloning and functional characterization of human vesicular RT glutamate transporter 3."; RL EMBO Rep. 3:798-803(2002). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Thymus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Heart, and Lung; 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=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 [6] RP VARIANT DFNA25 VAL-211. RX PubMed=18674745; DOI=10.1016/j.ajhg.2008.07.008; RA Ruel J., Emery S., Nouvian R., Bersot T., Amilhon B., Van Rybroek J.M., RA Rebillard G., Lenoir M., Eybalin M., Delprat B., Sivakumaran T.A., RA Giros B., El Mestikawy S., Moser T., Smith R.J.H., Lesperance M.M., RA Puel J.-L.; RT "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, RT underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in RT null mice."; RL Am. J. Hum. Genet. 83:278-292(2008). CC -!- FUNCTION: Multifunctional transporter that transports L-glutamate as CC well as multiple ions such as chloride, sodium and phosphate CC (PubMed:33440152, PubMed:12151341). At the synaptic vesicle membrane, CC mainly functions as an uniporter that mediates the uptake of L- CC glutamate into synaptic vesicles at presynaptic nerve terminals of CC excitatory neural cells (PubMed:12151341). The L-glutamate 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:12151341). In CC addition, functions as a chloride channel that allows a chloride CC permeation through the synaptic vesicle membrane that affects the CC proton electrochemical gradient and promotes synaptic vesicles CC acidification (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). The symporter activity is CC electrogenic (PubMed:33440152). Moreover, operates synergistically with CC SLC18A3/VACHT under a constant H(+) gradient, thereby allowing striatal CC vesicular acetylcholine uptake (By similarity). CC {ECO:0000250|UniProtKB:Q7TSF2, ECO:0000269|PubMed:12151341, 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:12151341}; 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=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823, CC ChEBI:CHEBI:17996; Evidence={ECO:0000250|UniProtKB:Q7TSF2}; CC -!- ACTIVITY REGULATION: The L-glutamate uniporter activity exhibits a CC biphasic dependence on chloride concentration. Chloride channel CC activity is allosterically activated by lumenal H(+) and Cl(-) leading CC to synaptic vesicles acidification. The glutamate transport activity is CC allosterically activated by lumenal H(+) and Cl(-), preventing non- CC vesicular L-glutamate release. {ECO:0000250|UniProtKB:Q7TSF2}. CC -!- INTERACTION: CC Q8NDX2-2; P78329: CYP4F2; NbExp=3; IntAct=EBI-17249797, EBI-1752413; CC Q8NDX2-2; A0PK00: TMEM120B; NbExp=3; IntAct=EBI-17249797, EBI-10171534; CC Q8NDX2-2; Q96EC8: YIPF6; NbExp=3; IntAct=EBI-17249797, EBI-751210; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle, synaptic CC vesicle membrane {ECO:0000250|UniProtKB:Q7TSF2}. Cell membrane CC {ECO:0000305|PubMed:33440152}; Multi-pass membrane protein CC {ECO:0000305}. Synapse, synaptosome {ECO:0000250|UniProtKB:Q7TSF2}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q8NDX2-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8NDX2-2; Sequence=VSP_033265; CC -!- TISSUE SPECIFICITY: Expressed in amygdala, cerebellum, hippocampus, CC medulla, spinal cord and thalamus. {ECO:0000269|PubMed:12151341}. CC -!- DISEASE: Deafness, autosomal dominant, 25 (DFNA25) [MIM:605583]: A form CC of non-syndromic sensorineural hearing loss. Sensorineural deafness CC results from damage to the neural receptors of the inner ear, the nerve CC pathways to the brain, or the area of the brain that receives sound CC information. DFNA25 expression is variable in terms of onset and rate CC of progression, with an age-dependent penetrance resembling an early- CC onset presbycusis, or senile deafness, a progressive bilateral loss of CC hearing that occurs in the aged. {ECO:0000269|PubMed:18674745}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the major facilitator superfamily. Sodium/anion CC cotransporter family. VGLUT subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AJ459241; CAD30553.1; -; mRNA. DR EMBL; AK128319; BAG54658.1; -; mRNA. DR EMBL; CH471054; EAW97637.1; -; Genomic_DNA. DR EMBL; BC117229; AAI17230.1; -; mRNA. DR EMBL; BC143396; AAI43397.1; -; mRNA. DR CCDS; CCDS44957.1; -. [Q8NDX2-2] DR CCDS; CCDS9077.1; -. [Q8NDX2-1] DR RefSeq; NP_001138760.1; NM_001145288.1. [Q8NDX2-2] DR RefSeq; NP_647480.1; NM_139319.2. [Q8NDX2-1] DR AlphaFoldDB; Q8NDX2; -. DR SMR; Q8NDX2; -. DR BioGRID; 128880; 13. DR IntAct; Q8NDX2; 4. DR STRING; 9606.ENSP00000316909; -. DR TCDB; 2.A.1.14.32; the major facilitator superfamily (mfs). DR GlyCosmos; Q8NDX2; 1 site, No reported glycans. DR GlyGen; Q8NDX2; 1 site. DR BioMuta; SLC17A8; -. DR DMDM; 74723817; -. DR EPD; Q8NDX2; -. DR MassIVE; Q8NDX2; -. DR PaxDb; 9606-ENSP00000316909; -. DR PeptideAtlas; Q8NDX2; -. DR Antibodypedia; 57947; 108 antibodies from 15 providers. DR DNASU; 246213; -. DR Ensembl; ENST00000323346.10; ENSP00000316909.4; ENSG00000179520.11. [Q8NDX2-1] DR Ensembl; ENST00000392989.3; ENSP00000376715.3; ENSG00000179520.11. [Q8NDX2-2] DR GeneID; 246213; -. DR KEGG; hsa:246213; -. DR MANE-Select; ENST00000323346.10; ENSP00000316909.4; NM_139319.3; NP_647480.1. DR UCSC; uc009ztx.4; human. [Q8NDX2-1] DR AGR; HGNC:20151; -. DR CTD; 246213; -. DR DisGeNET; 246213; -. DR GeneCards; SLC17A8; -. DR GeneReviews; SLC17A8; -. DR HGNC; HGNC:20151; SLC17A8. DR HPA; ENSG00000179520; Tissue enhanced (intestine, lymphoid tissue). DR MalaCards; SLC17A8; -. DR MIM; 605583; phenotype. DR MIM; 607557; gene. DR neXtProt; NX_Q8NDX2; -. DR OpenTargets; ENSG00000179520; -. DR Orphanet; 90635; Rare autosomal dominant non-syndromic sensorineural deafness type DFNA. DR PharmGKB; PA223010; -. DR VEuPathDB; HostDB:ENSG00000179520; -. DR eggNOG; KOG2532; Eukaryota. DR GeneTree; ENSGT00940000158187; -. DR HOGENOM; CLU_001265_5_0_1; -. DR InParanoid; Q8NDX2; -. DR OMA; VTTIFWN; -. DR OrthoDB; 2685946at2759; -. DR PhylomeDB; Q8NDX2; -. DR TreeFam; TF313535; -. DR PathwayCommons; Q8NDX2; -. DR Reactome; R-HSA-428643; Organic anion transporters. DR Reactome; R-HSA-5619076; Defective SLC17A8 causes autosomal dominant deafness 25 (DFNA25). DR Reactome; R-HSA-9662360; Sensory processing of sound by inner hair cells of the cochlea. DR SignaLink; Q8NDX2; -. DR BioGRID-ORCS; 246213; 8 hits in 1150 CRISPR screens. DR ChiTaRS; SLC17A8; human. DR GeneWiki; SLC17A8; -. DR GenomeRNAi; 246213; -. DR Pharos; Q8NDX2; Tbio. DR PRO; PR:Q8NDX2; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q8NDX2; Protein. DR Bgee; ENSG00000179520; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 62 other cell types or tissues. DR GO; GO:0097440; C:apical dendrite; IEA:Ensembl. DR GO; GO:0043679; C:axon terminus; IEA:Ensembl. DR GO; GO:0097441; C:basal dendrite; IEA:Ensembl. DR GO; GO:0034707; C:chloride channel complex; IEA:UniProtKB-KW. DR GO; GO:0060076; C:excitatory synapse; IBA:GO_Central. DR GO; GO:0097451; C:glial limiting end-foot; IEA:Ensembl. DR GO; GO:0005771; C:multivesicular body; IEA:Ensembl. DR GO; GO:1990030; C:pericellular basket; IEA:Ensembl. DR GO; GO:0043204; C:perikaryon; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030672; C:synaptic vesicle membrane; TAS:Reactome. 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:0005436; F:sodium:phosphate symporter activity; IDA:UniProtKB. DR GO; GO:0090102; P:cochlea development; IEA:Ensembl. DR GO; GO:0051938; P:L-glutamate import; ISS:UniProtKB. DR GO; GO:0015813; P:L-glutamate transmembrane transport; IDA: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:0003407; P:neural retina development; IEA:Ensembl. DR GO; GO:0098700; P:neurotransmitter loading into synaptic vesicle; IDA:SynGO. DR GO; GO:0055062; P:phosphate ion homeostasis; IDA:UniProtKB. DR GO; GO:0051951; P:positive regulation of glutamate uptake involved in transmission of nerve impulse; ISS:UniProtKB. DR GO; GO:0051631; P:regulation of acetylcholine uptake; ISS:UniProtKB. DR GO; GO:0050803; P:regulation of synapse structure or activity; IBA:GO_Central. DR GO; GO:0007605; P:sensory perception of sound; IEA:UniProtKB-KW. DR GO; GO:0044341; P:sodium-dependent phosphate transport; IC: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:SF207; VESICULAR GLUTAMATE TRANSPORTER 3; 1. DR Pfam; PF07690; MFS_1; 1. DR SUPFAM; SSF103473; MFS general substrate transporter; 1. DR PROSITE; PS50850; MFS; 1. DR Genevisible; Q8NDX2; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Chloride; Chloride channel; KW Cytoplasmic vesicle; Deafness; Disease variant; Glycoprotein; Hearing; KW Ion channel; Ion transport; Membrane; Neurotransmitter transport; KW Non-syndromic deafness; Phosphate transport; Reference proteome; Sodium; KW Sodium transport; Symport; Synapse; Synaptosome; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1..589 FT /note="Vesicular glutamate transporter 3" FT /id="PRO_0000331614" FT TOPO_DOM 1..76 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 77..97 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 98..130 FT /note="Vesicular" FT /evidence="ECO:0000255" FT TRANSMEM 131..151 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 152..153 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 154..174 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 175..182 FT /note="Vesicular" FT /evidence="ECO:0000255" FT TRANSMEM 183..203 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 204..221 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 222..242 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 243..249 FT /note="Vesicular" FT /evidence="ECO:0000255" FT TRANSMEM 250..270 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 271..314 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 315..335 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 336..353 FT /note="Vesicular" FT /evidence="ECO:0000255" FT TRANSMEM 354..374 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 375..390 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 391..411 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 412..413 FT /note="Vesicular" FT /evidence="ECO:0000255" FT TRANSMEM 414..434 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 435..447 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 448..468 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 469..481 FT /note="Vesicular" FT /evidence="ECO:0000255" FT TRANSMEM 482..502 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 503..586 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 40..61 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 559..589 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 106 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 302..351 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_033265" FT VARIANT 8 FT /note="T -> I (in dbSNP:rs45610843)" FT /id="VAR_042905" FT VARIANT 211 FT /note="A -> V (in DFNA25; dbSNP:rs121918339)" FT /evidence="ECO:0000269|PubMed:18674745" FT /id="VAR_054130" FT VARIANT 220 FT /note="A -> T (in dbSNP:rs11568530)" FT /id="VAR_054131" FT VARIANT 246 FT /note="G -> E (in dbSNP:rs11568543)" FT /id="VAR_054132" SQ SEQUENCE 589 AA; 64991 MW; E74DDC91495F8775 CRC64; MPFKAFDTFK EKILKPGKEG VKNAVGDSLG ILQRKIDGTT EEEDNIELNE EGRPVQTSRP SPPLCDCHCC GLPKRYIIAI MSGLGFCISF GIRCNLGVAI VEMVNNSTVY VDGKPEIQTA QFNWDPETVG LIHGSFFWGY IMTQIPGGFI SNKFAANRVF GAAIFLTSTL NMFIPSAARV HYGCVMCVRI LQGLVEGVTY PACHGMWSKW APPLERSRLA TTSFCGSYAG AVVAMPLAGV LVQYIGWSSV FYIYGMFGII WYMFWLLQAY ECPAAHPTIS NEEKTYIETS IGEGANVVSL SKFSTPWKRF FTSLPVYAII VANFCRSWTF YLLLISQPAY FEEVFGFAIS KVGLLSAVPH MVMTIVVPIG GQLADYLRSR QILTTTAVRK IMNCGGFGME ATLLLVVGFS HTKGVAISFL VLAVGFSGFA ISGFNVNHLD IAPRYASILM GISNGVGTLS GMVCPLIVGA MTRHKTREEW QNVFLIAALV HYSGVIFYGV FASGEKQEWA DPENLSEEKC GIIDQDELAE EIELNHESFA SPKKKMSYGA TSQNCEVQKK EWKGQRGATL DEEELTSYQN EERNFSTIS //