GPR65
entrez
8477
canonical
uniprot
Q8IYL9
canonical
ensembl
ENSG00000140030
resolver
ensp
ENSP00000267549
resolver
ensp
ENSP00000575224
resolver
enst
ENST00000267549
resolver
enst
ENST00000905165
resolver
genesymbol
GPR65
resolver
genesymbol_syn
TDAG8
resolver
hgnc
HGNC:4517
resolver
uniprot
B5B0C2
resolver
uniprot
O75819
resolver
uniprot_entry
B5B0C2_HUMAN
resolver
uniprot_entry
GPR65_HUMAN
resolver
uniprot_sec
O75819
resolver
activity_regulation
ACTIVITY REGULATION: Activated by a network of residues that connects an extracellular-facing cavity to Glu-142, a conserved charged residue buried in the transmembrane core of the receptor (PubMed:39753132). Protonation likely drives conformational changes in extracellular loop 2 (ECL2), which stabilizes movement of transmembrane 3 (TM3) and a series of rearrangements that connect the extracellular-facing cavity to Glu-142, a residue only conserved in proton-sensing G protein coupled receptors (PubMed:39753132). Activated by BTB09089, a positive allosteric modulator (PubMed:26550826). {ECO:0000269|PubMed:26550826, ECO:0000269|PubMed:39753132}.
uniprot
proteins
amino_acid_sequence
MNSTCIEEQHDLDHYLFPIVYIFVIIVSIPANIGSLCVSFLQAKKESELGIYLFSLSLSDLLYALTLPLWIDYTWNKDNWTFSPALCKGSAFLMYMNFYSSTAFLTCIAVDRYLAVVYPLKFFFLRTRRFALMVSLSIWILETIFNAVMLWEDETVVEYCDAEKSNFTLCYDKYPLEKWQINLNLFRTCTGYAIPLVTILICNRKVYQAVRHNKATENKEKKRIIKLLVSITVTFVLCFTPFHVMLLIRCILEHAVNFEDHSNSGKRTYTMYRITVALTSLNCVADPILYCFVTETGRYDMWNILKFCTGRCNTSQRQRKRILSVSTKDTMELEVLE
uniprot
proteins
function
FUNCTION: Proton-sensing G protein-coupled receptor activated by extracellular pH, which is required to monitor pH changes and generate adaptive reactions (PubMed:15326175, PubMed:15618224, PubMed:20855608, PubMed:33478938, PubMed:37722051, PubMed:39753132, PubMed:40211064). Activated by an optimal pH of 7.4 (PubMed:39753132). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase (PubMed:15326175, PubMed:15618224, PubMed:37722051, PubMed:39753132). GPR65 is mainly coupled to G(s) G proteins and mediates activation of adenylate cyclase activity (PubMed:15618224, PubMed:37722051, PubMed:39753132). May also act as a receptor for the glycosphingolipid psychosine (PSY) and several related glycosphingolipids (PubMed:11309421, PubMed:15326175). Plays a role in immune response by maintaining lysosome function and regulating T-cell metabolism (PubMed:27287411). Acts as a regulator of inflammation by mediating pH-sensing of extracellular acidification which takes place in inflamed tissues: activation regulates endo-lysosomal function of immune cells and T-cell metabolism (By similarity). Constitutively active in endosomes and stimulates adenylate cyclase production from endosomes independently from extracellular pH changes (PubMed:39753132). {ECO:0000250|UniProtKB:Q61038, ECO:0000269|PubMed:11309421, ECO:0000269|PubMed:15326175, ECO:0000269|PubMed:15618224, ECO:0000269|PubMed:20855608, ECO:0000269|PubMed:27287411, ECO:0000269|PubMed:33478938, ECO:0000269|PubMed:37722051, ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064}.
uniprot
proteins
mass_dalton
39333
uniprot
proteins
mutagenesis
MUTAGEN 10; /note="H->A: Impaired proton sensing ability."; /evidence="ECO:0000269|PubMed:40211064"; MUTAGEN 10; /note="H->F: Decreased proton-induced G protein-coupled receptor signaling; when associated with F-14 and F-243."; /evidence="ECO:0000269|PubMed:37722051"; MUTAGEN 14; /note="H->F: Decreased proton-induced G protein-coupled receptor signaling; when associated with F-10 and F-243."; /evidence="ECO:0000269|PubMed:37722051"; MUTAGEN 60; /note="D->N: Impaired ability to sense protons."; /evidence="ECO:0000269|PubMed:33478938"; MUTAGEN 78; /note="D->A: Impaired proton sensing ability."; /evidence="ECO:0000269|PubMed:40211064"; MUTAGEN 87; /note="C->A: Abolished proton sensing ability."; /evidence="ECO:0000269|PubMed:40211064"; MUTAGEN 142; /note="E->Q: Mimics the protonation state; induces a shift of the optimal pH for activation."; /evidence="ECO:0000269|PubMed:33478938, ECO:0000269|PubMed:39753132"; MUTAGEN 160; /note="C->A: Abolished proton sensing ability."; /evidence="ECO:0000269|PubMed:40211064"; MUTAGEN 172; /note="D->A: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064"; MUTAGEN 243; /note="H->F: Decreased activation by protons. Decreased proton-induced G protein-coupled receptor signaling; when associated with F-10 and F-14."; /evidence="ECO:0000269|PubMed:37722051, ECO:0000269|PubMed:40211064"; MUTAGEN 273; /note="R->A: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064"; MUTAGEN 286; /note="D->N: Impaired ability to sense protons."; /evidence="ECO:0000269|PubMed:33478938
uniprot
proteins
protein_family
G protein-coupled receptor 1 family
uniprot
proteins
pubmed
11309421
uniprot
proteins
pubmed
12508121
uniprot
proteins
pubmed
15326175
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15618224
uniprot
proteins
pubmed
20855608
uniprot
proteins
pubmed
26550826
uniprot
proteins
pubmed
27287411
uniprot
proteins
pubmed
33478938
uniprot
proteins
pubmed
37722051
uniprot
proteins
pubmed
39753132
uniprot
proteins
pubmed
40211064
uniprot
proteins
pubmed
9655242
uniprot
proteins
sequence_length
337
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15618224, ECO:0000269|PubMed:37722051}; Multi-pass membrane protein {ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064}. Early endosome membrane {ECO:0000269|PubMed:37722051}; Multi-pass membrane protein {ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064}. Late endosome membrane {ECO:0000269|PubMed:37722051}; Multi-pass membrane protein {ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064}. Note=Internalizes and localizes to early and late endosomes, from where GPR65 signals at steady state, irrespective of extracellular pH (PubMed:39753132). Changes in extracellular pH may relocalize receptor signaling to the cell membrane (PubMed:39753132). {ECO:0000269|PubMed:39753132}.
uniprot
proteins
transmembrane_region
TRANSMEM 6..42; /note="Helical; Name=1"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0007744|PDB:9BHL"; TRANSMEM 47..77; /note="Helical; Name=2"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0007744|PDB:9BHL"; TRANSMEM 83..118; /note="Helical; Name=3"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0007744|PDB:9BHL"; TRANSMEM 127..153; /note="Helical; Name=4"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0007744|PDB:9BHL"; TRANSMEM 175..212; /note="Helical; Name=5"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0007744|PDB:9BHL"; TRANSMEM 217..252; /note="Helical; Name=6"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0007744|PDB:9BHL"; TRANSMEM 265..293; /note="Helical; Name=7"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0007744|PDB:9BHL
uniprot
proteins