{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q15743","secondaryAccessions":["Q13334","Q4VBB4","Q6IX34"],"uniProtkbId":"GPR68_HUMAN","entryAudit":{"firstPublicDate":"1998-07-15","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"1996-11-01","entryVersion":194,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"27693231"}],"value":"G protein-coupled receptor 68"}},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"7498459"}],"value":"G protein-coupled receptor 12A"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"7498459"}],"value":"GPR12A"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"8661159"}],"value":"Ovarian cancer G protein-coupled receptor 1"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"8661159"}],"value":"OGR-1"}]}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"27693231"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:4519"}],"value":"GPR68"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"8661159"}],"value":"OGR1"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q8BFQ3"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12955148"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29677517"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30471999"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32865988"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33478938"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39753132"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40215959"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40215960"}],"value":"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)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26550826"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31298539"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32865988"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39753132"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39900965"}],"value":"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)"}],"commentType":"ACTIVITY REGULATION"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q15743","intActId":"EBI-64069552"},"interactantTwo":{"uniProtKBAccession":"O60894","geneName":"RAMP1","intActId":"EBI-962893"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q15743","intActId":"EBI-64069552"},"interactantTwo":{"uniProtKBAccession":"O60895","geneName":"RAMP2","intActId":"EBI-9009040"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q15743","intActId":"EBI-64069552"},"interactantTwo":{"uniProtKBAccession":"O60896","geneName":"RAMP3","intActId":"EBI-720447"},"numberOfExperiments":2,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39753132"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39753132"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40215959"}],"value":"Multi-pass membrane protein","id":"SL-9909"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12955148"}],"value":"Found at low level in a wide range of tissues, but significantly expressed in lung, kidney, bone and nervous system"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12955148"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33478938"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39753132"}],"value":"A multitude of proton-sensing residues, which include extracellular histidine residues (His-17, His-20, His-84, His-169 and His-269) or triad of buried acidic residues (Asp-67, Glu-149 and Asp-282), contribute to activation of the G protein-coupled receptor activity and pH sensitivity"}],"commentType":"DOMAIN"},{"commentType":"DISEASE","disease":{"diseaseId":"Amelogenesis imperfecta, hypomaturation type, 2A6","diseaseAccession":"DI-04871","acronym":"AI2A6","description":"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.","diseaseCrossReference":{"database":"MIM","id":"617217"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27693231"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32279993"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35055328"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38761453"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00521"}],"value":"Belongs to the G protein-coupled receptor 1 family"}],"commentType":"SIMILARITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"10806476"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"16508674"}],"value":"Was originally thought to be a receptor for sphingosylphosphorylcholine (SPC) (PubMed:10806476). However, this work has been retracted (PubMed:16508674)"}],"commentType":"CAUTION"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"AAH96071.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"AAH96072.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"AAH96073.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"AAH96074.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"AAH98567.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"AAT38917.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"ACG60649.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"EAW81447.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"WEB RESOURCE","resourceName":"Atlas of Genetics and Cytogenetics in Oncology and Haematology","resourceUrl":"https://atlasgeneticsoncology.org/gene/40745/GPR68","ftp":false}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":365,"modifier":"EXACT"}},"description":"G protein-coupled receptor 68","featureId":"PRO_0000070113"},{"type":"Topological domain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":12,"modifier":"EXACT"}},"description":"Extracellular","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39753132"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40215959"},{"evidenceCode":"ECO:0007744","source":"PDB","id":"9BHM"},{"evidenceCode":"ECO:0007744","source":"PDB","id":"9BI6"}]},{"type":"Transmembrane","location":{"start":{"value":13,"modifier":"EXACT"},"end":{"value":49,"modifier":"EXACT"}},"description":"Helical; 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