GPR4
entrez
2828
canonical
uniprot
P46093
canonical
ensembl
ENSG00000177464
resolver
ensp
ENSP00000319744
resolver
ensp
ENSP00000547443
resolver
ensp
ENSP00000547444
resolver
ensp
ENSP00000547445
resolver
ensp
ENSP00000547446
resolver
ensp
ENSP00000547447
resolver
ensp
ENSP00000547448
resolver
enst
ENST00000323040
resolver
enst
ENST00000877384
resolver
enst
ENST00000877385
resolver
enst
ENST00000877386
resolver
enst
ENST00000877387
resolver
enst
ENST00000877388
resolver
enst
ENST00000877389
resolver
genesymbol
GPR4
resolver
hgnc
HGNC:4497
resolver
uniprot
A8K3T3
resolver
uniprot
B0M0K1
resolver
uniprot
Q6NWM4
resolver
uniprot_entry
GPR4_HUMAN
resolver
uniprot_sec
A8K3T3
resolver
uniprot_sec
B0M0K1
resolver
uniprot_sec
Q6NWM4
resolver
activity_regulation
ACTIVITY REGULATION: Activated by a network of residues that connects an extracellular-facing cavity to Glu-145, 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-145, a residue only conserved in proton-sensing G protein coupled receptors (PubMed:39753132). Inhibited by the antagonist NE52-QQ57, which prevents activation by protons (PubMed:40211064, PubMed:40215960). {ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215960}.
uniprot
proteins
amino_acid_sequence
MGNHTWEGCHVDSRVDHLFPPSLYIFVIGVGLPTNCLALWAAYRQVQQRNELGVYLMNLSIADLLYICTLPLWVDYFLHHDNWIHGPGSCKLFGFIFYTNIYISIAFLCCISVDRYLAVAHPLRFARLRRVKTAVAVSSVVWATELGANSAPLFHDELFRDRYNHTFCFEKFPMEGWVAWMNLYRVFVGFLFPWALMLLSYRGILRAVRGSVSTERQEKAKIKRLALSLIAIVLVCFAPYHVLLLSRSAIYLGRPWDCGFEERVFSAYHSSLAFTSLNCVADPILYCLVNEGARSDVAKALHNLLRFLASDKPQEMANASLTLETPLTSKRNSTAKAMTGSWAATPPSQGDQVQLKMLPPAQ
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:12955148, PubMed:17462861, PubMed:33478938, PubMed:39753132, PubMed:39799123, PubMed:40211064, PubMed:40215959, PubMed:40215960). Activated by an optimal pH of 6.8-7.2 (PubMed:12955148, PubMed:17462861, 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:39753132, PubMed:40211064, PubMed:40215960). GPR4 is mainly coupled to G(s) G proteins and mediates activation of adenylate cyclase activity (PubMed:12955148, PubMed:17462861, PubMed:20211729, PubMed:22110680, PubMed:39753132, PubMed:40211064, PubMed:40215960). May also couple with G(i), G(q) and G(12)/G(13) G proteins (PubMed:12955148, PubMed:17462861, PubMed:20211729, PubMed:22110680). Acts as a key regulator of respiratory sensitivity to CO2/H(+) in brain retrotrapezoid nucleus neurons: acts by mediating detection of protons generated by the formation of carbonic acid in the blood, an important mechanism to impulse to breathe (By similarity). Also acts as a regulator of acid secretion in the kidney collecting duct by maintaining acid-base homeostasis in the kidney (By similarity). Acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells, possibly through the G(12)/G(13)/Rho GTPase signaling pathway (PubMed:32058960). {ECO:0000250|UniProtKB:Q8BUD0, ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:17462861, ECO:0000269|PubMed:20211729, ECO:0000269|PubMed:22110680, ECO:0000269|PubMed:32058960, ECO:0000269|PubMed:33478938, ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:39799123, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960}.
uniprot
proteins
mass_dalton
40982
uniprot
proteins
mutagenesis
MUTAGEN 4; /note="H->Y: No effect on pH-sensing activity."; /evidence="ECO:0000269|PubMed:20211729"; MUTAGEN 10; /note="H->Y: No effect on pH-sensing activity."; /evidence="ECO:0000269|PubMed:20211729"; MUTAGEN 17; /note="H->Y: No effect on pH-sensing activity."; /evidence="ECO:0000269|PubMed:20211729, ECO:0000269|PubMed:40215959"; MUTAGEN 24; /note="Y->A: Reduced inhibition by antagonist NE52-QQ57."; /evidence="ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215960"; MUTAGEN 45; /note="Q->A: Induces a shift of the optimal pH for activation."; /evidence="ECO:0000269|PubMed:39799123"; MUTAGEN 51; /note="E->A: Induces a shift of the optimal pH for activation."; /evidence="ECO:0000269|PubMed:39799123"; MUTAGEN 63; /note="D->N: Impaired ability to sense protons."; /evidence="ECO:0000269|PubMed:33478938, ECO:0000269|PubMed:40211064"; MUTAGEN 73; /note="W->A: Reduced inhibition by antagonist NE52-QQ57."; /evidence="ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215960"; MUTAGEN 76; /note="Y->A: Reduced inhibition by antagonist NE52-QQ57."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 77; /note="F->A: Reduced inhibition by antagonist NE52-QQ57."; /evidence="ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215960"; MUTAGEN 79; /note="H->A: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:40215959"; MUTAGEN 79; /note="H->Y: Displays smaller cAMP, rho, PLC responses to mildly alkaline to acidic pH of 7.1 but almost the same or higher responses to severely acidic pH values of 6.5-6.2."; /evidence="ECO:0000269|PubMed:20211729"; MUTAGEN 80; /note="H->A: Does not affect sensitivity to protons."; /evidence="ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960"; MUTAGEN 80; /note="H->Y: No effect on pH-sensing activity."; /evidence="ECO:0000269|PubMed:20211729"; MUTAGEN 85; /note="H->A: Does not affect sensitivity to protons."; /evidence="ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960"; MUTAGEN 85; /note="H->Y: No effect on pH-sensing activity."; /evidence="ECO:0000269|PubMed:20211729"; MUTAGEN 100; /note="N->A: Increased potency of protons."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 115; /note="R->A: Decreased proton-induced G protein-coupled receptor activity. Endothelial permeability is decreased under acid conditions."; /evidence="ECO:0000269|PubMed:22110680, ECO:0000269|PubMed:32058960, ECO:0000269|PubMed:39799123"; MUTAGEN 129; /note="R->A: Induces a shift of the optimal pH for activation."; /evidence="ECO:0000269|PubMed:39799123"; MUTAGEN 145; /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 155; /note="H->A: Does not affect sensitivity to protons."; /evidence="ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960"; MUTAGEN 156; /note="D->A: Increased basal activity and proton potencies."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 161; /note="D->N: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:40215959"; MUTAGEN 162; /note="R->A: Increased basal activity and proton potencies."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 165; /note="H->A,F: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959"; MUTAGEN 165; /note="H->Y: Displays smaller cAMP, rho, PLC responses to mildly alkaline to acidic pH of 7.1 but almost the same or higher responses to severely acidic pH values of 6.5-6.2."; /evidence="ECO:0000269|PubMed:20211729"; MUTAGEN 167; /note="F->A: Decreased sensitivity to protons."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 169; /note="F->A: Decreased sensitivity to protons."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 170; /note="E->A: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132"; MUTAGEN 172; /note="F->A: Decreased sensitivity to protons."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 218; /note="E->A: Induces a shift of the optimal pH for activation."; /evidence="ECO:0000269|PubMed:39799123"; MUTAGEN 233; /note="V->A: Impaired proton-induced activation."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 237; /note="F->A: Impaired proton-induced activation."; /evidence="ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215960"; MUTAGEN 241; /note="H->F: Impaired response to protons."; /evidence="ECO:0000269|PubMed:40211064"; MUTAGEN 269; /note="H->A,F: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959"; MUTAGEN 269; /note="H->Y: Displays smaller cAMP, rho, PLC responses to mildly alkaline to acidic pH of 7.1 but almost the same or higher responses to severely acidic pH values of 6.5-6.2."; /evidence="ECO:0000269|PubMed:20211729"; MUTAGEN 282; /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
11535583
uniprot
proteins
pubmed
12955148
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15057824
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16498716
uniprot
proteins
pubmed
17462861
uniprot
proteins
pubmed
20211729
uniprot
proteins
pubmed
22110680
uniprot
proteins
pubmed
32058960
uniprot
proteins
pubmed
33478938
uniprot
proteins
pubmed
39753132
uniprot
proteins
pubmed
39799123
uniprot
proteins
pubmed
40211064
uniprot
proteins
pubmed
40215959
uniprot
proteins
pubmed
40215960
uniprot
proteins
pubmed
7498459
uniprot
proteins
pubmed
7832990
uniprot
proteins
pubmed
8595909
uniprot
proteins
sequence_length
362
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:17462861, ECO:0000269|PubMed:20211729}; Multi-pass membrane protein {ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960}.
uniprot
proteins
transmembrane_region
TRANSMEM 9..45; /note="Helical; Name=1"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960, ECO:0007744|PDB:9BIP"; TRANSMEM 50..80; /note="Helical; Name=2"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960, ECO:0007744|PDB:9BIP"; TRANSMEM 86..121; /note="Helical; Name=3"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960, ECO:0007744|PDB:9BIP"; TRANSMEM 130..156; /note="Helical; Name=4"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960, ECO:0007744|PDB:9BIP"; TRANSMEM 173..210; /note="Helical; Name=5"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960, ECO:0007744|PDB:9BIP"; TRANSMEM 215..250; /note="Helical; Name=6"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960, ECO:0007744|PDB:9BIP"; TRANSMEM 261..289; /note="Helical; Name=7"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40211064, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960, ECO:0007744|PDB:9BIP
uniprot
proteins