GPR68
entrez
8111
canonical
uniprot
Q15743
canonical
ensembl
ENSG00000119714
resolver
ensp
ENSP00000434045
resolver
ensp
ENSP00000440797
resolver
ensp
ENSP00000498702
resolver
ensp
ENSP00000574112
resolver
ensp
ENSP00000574113
resolver
ensp
ENSP00000574114
resolver
ensp
ENSP00000574115
resolver
ensp
ENSP00000764298
resolver
ensp
ENSP00000789311
resolver
enst
ENST00000531499
resolver
enst
ENST00000535815
resolver
enst
ENST00000650645
resolver
enst
ENST00000904053
resolver
enst
ENST00000904054
resolver
enst
ENST00000904055
resolver
enst
ENST00000904056
resolver
genesymbol
GPR68
resolver
genesymbol_syn
OGR1
resolver
hgnc
HGNC:4519
resolver
uniprot
A1A5B2
resolver
uniprot
Q13334
resolver
uniprot
Q4VBB4
resolver
uniprot
Q6IX34
resolver
uniprot_entry
A1A5B2_HUMAN
resolver
uniprot_entry
GPR68_HUMAN
resolver
uniprot_sec
Q13334
resolver
uniprot_sec
Q4VBB4
resolver
uniprot_sec
Q6IX34
resolver
activity_regulation
ACTIVITY REGULATION: Activated by a network of residues that connects an extracellular-facing cavity to Glu-149, 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-149, a residue only conserved in proton-sensing G protein coupled receptors (PubMed:39753132). Activated in an allosteric manner by divalent metal ions at the extracellular surface following the order: Cd(2+) > Co(2+) > Ni(2+) > Zn(2+) > Fe(2+) > Ca(2+) > Mg(2+) (PubMed:32865988). Activated by the benzodiazepine drug lorazepam, a non-selective GPR68 positive allosteric modulator (PubMed:26550826). Activated by ogerin (ZINC67740571), a selective GPR68 positive allosteric modulator (PubMed:26550826). Activated by small molecule MS48107, a selective positive allosteric modulator (PubMed:31298539). Inhibited by small molecule ogremorphin, inducing ferroptosis in cancer cells (PubMed:39900965). {ECO:0000269|PubMed:26550826, ECO:0000269|PubMed:31298539, ECO:0000269|PubMed:32865988, ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:39900965}.
uniprot
proteins
amino_acid_sequence
MGNITADNSSMSCTIDHTIHQTLAPVVYVTVLVVGFPANCLSLYFGYLQIKARNELGVYLCNLTVADLFYICSLPFWLQYVLQHDNWSHGDLSCQVCGILLYENIYISVGFLCCISVDRYLAVAHPFRFHQFRTLKAAVGVSVVIWAKELLTSIYFLMHEEVIEDENQHRVCFEHYPIQAWQRAINYYRFLVGFLFPICLLLASYQGILRAVRRSHGTQKSRKDQIQRLVLSTVVIFLACFLPYHVLLLVRSVWEASCDFAKGVFNAYHFSLLLTSFNCVADPVLYCFVSETTHRDLARLRGACLAFLTCSRTGRAREAYPLGAPEASGKSGAQGEEPELLTKLHPAFQTPNSPGSGGFPTGRLA
uniprot
proteins
disease_involvement
DISEASE: Amelogenesis imperfecta, hypomaturation type, 2A6 (AI2A6) [MIM:617217]: A defect of enamel formation. The disorder involves both primary and secondary dentitions. The teeth have a shiny agar jelly appearance and the enamel is softer than normal. Brown pigment is present in middle layers of enamel. {ECO:0000269|PubMed:27693231, ECO:0000269|PubMed:32279993, ECO:0000269|PubMed:35055328, ECO:0000269|PubMed:38761453}. Note=The disease is caused by variants affecting the gene represented in this entry.
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:29677517, PubMed:32865988, PubMed:33478938, PubMed:39753132, PubMed:40215959, PubMed:40215960). The receptor is almost silent at pH 7.8 but fully activated at pH 6.8 (PubMed:12955148, 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 phospholipase C (PubMed:29677517, PubMed:39753132). GPR68 is mainly coupled to G(q) G proteins and mediates production of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (PubMed:29677517, PubMed:39753132). Acts as a key mechanosensor of fluid shear stress and membrane stretch (PubMed:29677517, PubMed:30471999). Expressed in endothelial cells of small-diameter resistance arteries, where it mediates flow-induced dilation in response to shear stress (PubMed:29677517). May represents an osteoblastic pH sensor regulating cell-mediated responses to acidosis in bone (By similarity). Acts as a regulator of calcium-sensing receptor CASR in a seesaw manner: GPR68-mediated signaling inhibits CASR signaling in response to protons, while CASR inhibits GPR68 in presence of extracellular calcium (By similarity). {ECO:0000250|UniProtKB:Q8BFQ3, ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:29677517, ECO:0000269|PubMed:30471999, ECO:0000269|PubMed:32865988, ECO:0000269|PubMed:33478938, ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959, ECO:0000269|PubMed:40215960}.
uniprot
proteins
mass_dalton
41077
uniprot
proteins
mutagenesis
MUTAGEN 13; /note="C->A: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 17; /note="H->A: No effect on pH-sensing activity."; /evidence="ECO:0000269|PubMed:40215959"; MUTAGEN 17; /note="H->F: Decreased but not abolished proton-induced G protein-coupled receptor signaling. Failed to stimulate IP formation at pH 6.8, activity is restored at more acid pH. Abolished response to shear stress."; /evidence="ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:29677517, ECO:0000269|PubMed:32865988"; MUTAGEN 20; /note="H->A: Decreased but not abolished proton-induced G protein-coupled receptor signaling. Abolished response to shear stress."; /evidence="ECO:0000269|PubMed:29677517, ECO:0000269|PubMed:32865988, ECO:0000269|PubMed:39753132"; MUTAGEN 20; /note="H->F: Failed to stimulate IP formation at pH 6.8, activity is restored at more acid pH."; /evidence="ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:40215959"; MUTAGEN 67; /note="D->N: Impaired ability to sense protons."; /evidence="ECO:0000269|PubMed:33478938"; MUTAGEN 84; /note="H->F: Decreased but not abolished proton-induced G protein-coupled receptor signaling. Failed to stimulate IP formation at pH 6.8, activity is restored at more acid pH. Abolished response to shear stress."; /evidence="ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:29677517, ECO:0000269|PubMed:32865988, ECO:0000269|PubMed:40215959"; MUTAGEN 85; /note="D->A: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:40215959"; MUTAGEN 89; /note="H->F,A: No effect on pH-sensing activity."; /evidence="ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:40215959"; MUTAGEN 102; /note="Y->A: Abolished proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132"; MUTAGEN 118; /note="D->A: Increased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132"; MUTAGEN 127; /note="F->A: Abolished proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132"; MUTAGEN 149; /note="E->Q: Mimics the protonation state; more easily activated by protons."; /evidence="ECO:0000269|PubMed:33478938, ECO:0000269|PubMed:39753132"; MUTAGEN 159; /note="H->F,A: No effect on pH-sensing activity."; /evidence="ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:40215959"; MUTAGEN 165; /note="D->A: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:40215959"; MUTAGEN 169; /note="H->F,A: Decreased but not abolished proton-induced G protein-coupled receptor signaling. Failed to stimulate IP formation at pH 6.8, activity is restored at more acid pH. Abolished response to shear stress."; /evidence="ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:29677517, ECO:0000269|PubMed:32865988, ECO:0000269|PubMed:40215959"; MUTAGEN 174; /note="E->A: Abolished proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959"; MUTAGEN 175; /note="H->F,A: No effect on pH-sensing activity."; /evidence="ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:40215959"; MUTAGEN 240; /note="C->A: Increased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132"; MUTAGEN 241; /note="F->A: Increased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132"; MUTAGEN 245; /note="H->F: Decreased but not abolished proton-induced G protein-coupled receptor signaling. Severe loss pH-sensing activity."; /evidence="ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:32865988"; MUTAGEN 258; /note="C->A: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:40215960"; MUTAGEN 269; /note="H->A: Abolished proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959"; MUTAGEN 269; /note="H->F: Decreased but not abolished proton-induced G protein-coupled receptor signaling. Failed to stimulate IP formation at pH 6.8, activity is restored at more acid pH."; /evidence="ECO:0000269|PubMed:12955148, ECO:0000269|PubMed:32865988"; MUTAGEN 282; /note="D->A: Decreased proton-induced G protein-coupled receptor signaling."; /evidence="ECO:0000269|PubMed:39753132"; 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
10806476
uniprot
proteins
pubmed
12508121
uniprot
proteins
pubmed
12955148
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16508674
uniprot
proteins
pubmed
21248752
uniprot
proteins
pubmed
26550826
uniprot
proteins
pubmed
27693231
uniprot
proteins
pubmed
29677517
uniprot
proteins
pubmed
30471999
uniprot
proteins
pubmed
31298539
uniprot
proteins
pubmed
32279993
uniprot
proteins
pubmed
32865988
uniprot
proteins
pubmed
33478938
uniprot
proteins
pubmed
35055328
uniprot
proteins
pubmed
38761453
uniprot
proteins
pubmed
39753132
uniprot
proteins
pubmed
39900965
uniprot
proteins
pubmed
40215959
uniprot
proteins
pubmed
40215960
uniprot
proteins
pubmed
7498459
uniprot
proteins
pubmed
8661159
uniprot
proteins
sequence_length
365
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:39753132}; Multi-pass membrane protein {ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959}.
uniprot
proteins
transmembrane_region
TRANSMEM 13..49; /note="Helical; Name=1"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959, ECO:0007744|PDB:9BHM, ECO:0007744|PDB:9BI6"; TRANSMEM 54..84; /note="Helical; Name=2"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959, ECO:0007744|PDB:9BHM, ECO:0007744|PDB:9BI6"; TRANSMEM 90..125; /note="Helical; Name=3"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959, ECO:0007744|PDB:9BHM, ECO:0007744|PDB:9BI6"; TRANSMEM 134..160; /note="Helical; Name=4"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959, ECO:0007744|PDB:9BHM, ECO:0007744|PDB:9BI6"; TRANSMEM 177..214; /note="Helical; Name=5"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959, ECO:0007744|PDB:9BHM, ECO:0007744|PDB:9BI6"; TRANSMEM 219..254; /note="Helical; Name=6"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959, ECO:0007744|PDB:9BHM, ECO:0007744|PDB:9BI6"; TRANSMEM 261..289; /note="Helical; Name=7"; /evidence="ECO:0000269|PubMed:39753132, ECO:0000269|PubMed:40215959, ECO:0007744|PDB:9BHM, ECO:0007744|PDB:9BI6
uniprot
proteins