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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 362 | 19q13.32 | GPR4 | G protein-coupled receptor 4 | 11,21 |
| Mouse | 7 | 365 | 7 A3 | Gpr4 | G protein-coupled receptor 4 | |
| Rat | 7 | 365 | 1q21 | Gpr4 | G protein-coupled receptor 4 | |
| Previous and Unofficial Names |
| GPR19 | G-protein coupled receptor 19 |
| Database Links |
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| Specialist databases | |
| GPCRdb | gpr4_human (Hs), gpr4_mouse (Mm), gpr4_rat (Rn) |
| Other databases | |
| Alphafold | P46093 (Hs), Q8BUD0 (Mm), Q4KLH9 (Rn) |
| ChEMBL Target | CHEMBL3638324 (Hs), CHEMBL4105764 (Mm), CHEMBL4105950 (Rn) |
| Ensembl Gene | ENSG00000177464 (Hs), ENSMUSG00000044317 (Mm), ENSRNOG00000016362 (Rn) |
| Entrez Gene | 2828 (Hs), 319197 (Mm), 308408 (Rn) |
| Human Protein Atlas | ENSG00000177464 (Hs) |
| KEGG Gene | hsa:2828 (Hs), mmu:319197 (Mm), rno:308408 (Rn) |
| OMIM | 600551 (Hs) |
| Pharos | P46093 (Hs) |
| RefSeq Nucleotide | NM_005282 (Hs), NM_175668 (Mm), NM_001025680 (Rn) |
| RefSeq Protein | NP_005273 (Hs), NP_783599 (Mm), NP_001020851 (Rn) |
| UniProtKB | P46093 (Hs), Q8BUD0 (Mm), Q4KLH9 (Rn) |
| Wikipedia | GPR4 (Hs) |
| Natural/Endogenous Ligands |
| Protons |
| Comments: The role of GPR4 as a proton-sensing receptor is supported by several publications. |
Download all structure-activity data for this target as a CSV file 
| Agonist Comments | ||
| A report that sphingosylphosphorylcholine (SPC) and lysophosphatidylcholine (LPC) were ligands for GPR4 [38] was subsequently retracted [24]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [6,28]. |
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| In an assay measuring cAMP accumulation in GPR4-transfected CHO cells, psychosine was shown to competivitely inhibit the cAMP accumulation induced by proton-stimulation of GPR4 [34]. This effect is seen with other proton-sensing receptors. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Immunopharmacology Comments |
| GPR4 is a proton sensing GPCR with emerging roles in a range of physiological processes [19], including sensing and initiating responses to tissue acidosis. Pathophysiological states such as inflammation [16], tumours, ischemia, metabolic, and respiratory disease are commonly accompanied by tissue acidosis. Activation of GPR4 at acid pH stimulates the expression of inflammatory modulators such as chemokines, cytokines, and adhesion molecules, which significantly impacts cellular and humoural immune functions [7]. Both pharmacological and genetic disruption of GPR4 produce broadly anti-inflammatory effects [27,33,35], adding further evidence that GPR4 is a pro-inflammatory GPCR. Thus, antagonists are being developed to test the validity of GPR4 blockade as a therapeutically effective mechanism to treat inflammatory conditions. |
| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
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Gs family Gi/Go family Gq/G11 family G12/G13 family |
Adenylyl cyclase stimulation Phospholipase C stimulation |
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Comments:
Coupling to Gs-induced cAMP formation following activation by protons [18-19,31]. Coupling to the G12/13/Rho signalling pathway and the Gq/PLC signalling pathway have also been reported [18]. Histidine residues at positions 79, 165 and 269 are important for the receptor's coupling to multiple signalling pathways [18]. |
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| References: 29 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||||
| Northern blot analysis failed to detect GPR4 in the putamen, pons, frontal cortex, hypothalamus, hippocampus, thalamus or cerebellum [11]. Not detected by RT-PCR in MG63 human osteosarcoma cells [19]. RT-PCR analysis showed that GPR4 is not expressed on mature or immature human monocytes [17]. Not detected in human neutrophils by RT-PCR [23]. Expression is increased in human microvascular endothelial cells (HBMEC) in conditions of inflammatory stress. Expression levels are higher in HBMEC than in dermal microvascular endothelial cells [20]. GPR4 expression levels are higher post-infection. Extracellular acidosis is often associated with immunopathologies, suggesting a role for acid-sensing receptors in response to infection [26]. The expression of GPR4 in dorsal root ganglion neurons suggests a role for the receptor in nociception [12]. |
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| Expression Datasets |
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| Functional Assays
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| Functional Assay Comments | ||||||||||
| The findings of Bektas et al. support others in showing GPR4 is not a lysophospholipid receptor. cAMP elevation is activated in response to detection of a low extracellular pH [34]. |
| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| Experiments in knockout mice demonstrating in metabolic acidosis resulting from impaired kidney function implicate GPR4 as having an important role as a proton-sensing receptor in the kidney [30]. Codina et al. speculate that pH-activated GPR4 plays a role in the homeostatic regulation of acid-base balance, by means of increasing H(+)-K(+)-ATPase α-subunit (ATP4A) via increased PKA activity [5]. |
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| Phenotypes, Alleles and Disease Models
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| Biologically Significant Variants
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| General Comments |
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The role of GPR4 as a proton-sensing receptor is supported by several publications [6,28]. Several studies state that GPR4 is a member of a GPCR orphan receptor subfamily with GPR65, GPR68 and GPR132 and that these receptors will be targets for the development of new anti-cancer small molecule drugs [29]. There is an overlapping expression pattern between the members of this GPCR subfamily [29]. N-terminal histidine residues of the receptor are shown to be important in the receptor's function within certain pH ranges. It has been shown by mutagenesis experiments- His-174 and His-259 are conserved across this receptor subfamily and are required for the role in acid-sensing [22]. The structural features essential for acid induction of inositol phosphate formation displayed by GPR68 are conserved in GPR4 suggesting a wider role for the receptor. CuCl2 binds to the conserved histidine residues in OGR1 therefor GPR4 may also be activated by CuCl2. The broad expression pattern of GPR4 suggests its role as an acid-sensing receptor is involved in a wider range of physiological processes than the specific acid-sensing ion channels with an established role in nociception [19]. |
1. Afrasiabi E, Blom T, Ekokoski E, Tuominen RK, Törnquist K. (2006) Sphingosylphosphorylcholine enhances calcium entry in thyroid FRO cells by a mechanism dependent on protein kinase C. Cell Signal, 18 (10): 1671-8. [PMID:16490345]
2. Bektas M, Barak LS, Jolly PS, Liu H, Lynch KR, Lacana E, Suhr KB, Milstien S, Spiegel S. (2003) The G protein-coupled receptor GPR4 suppresses ERK activation in a ligand-independent manner. Biochemistry, 42 (42): 12181-91. [PMID:14567679]
3. Castellone RD, Leffler NR, Dong L, Yang LV. (2011) Inhibition of tumor cell migration and metastasis by the proton-sensing GPR4 receptor. Cancer Lett, 312 (2): 197-208. [PMID:21917373]
4. Chen A, Dong L, Leffler NR, Asch AS, Witte ON, Yang LV. (2011) Activation of GPR4 by acidosis increases endothelial cell adhesion through the cAMP/Epac pathway. PLoS ONE, 6 (11): e27586. [PMID:22110680]
5. Codina J, Opyd TS, Powell ZB, Furdui CM, Petrovic S, Penn RB, DuBose TD. (2011) pH-dependent regulation of the α-subunit of H+-K+-ATPase (HKα2). Am J Physiol Renal Physiol, 301 (3): F536-43. [PMID:21653633]
6. Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR et al.. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev, 65 (3): 967-86. [PMID:23686350]
7. Dong L, Li Z, Leffler NR, Asch AS, Chi JT, Yang LV. (2013) Acidosis activation of the proton-sensing GPR4 receptor stimulates vascular endothelial cell inflammatory responses revealed by transcriptome analysis. PLoS ONE, 8 (4): e61991. [PMID:23613998]
8. Frick KK, Krieger NS, Nehrke K, Bushinsky DA. (2009) Metabolic acidosis increases intracellular calcium in bone cells through activation of the proton receptor OGR1. J Bone Miner Res, 24 (2): 305-13. [PMID:18847331]
9. Fukuda H, Ito S, Watari K, Mogi C, Arisawa M, Okajima F, Kurose H, Shuto S. (2016) Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction. ACS Med Chem Lett, 7 (5): 493-7. [PMID:27190599]
10. Hasegawa H, Lei J, Matsumoto T, Onishi S, Suemori K, Yasukawa M. (2011) Lysophosphatidylcholine enhances the suppressive function of human naturally occurring regulatory T cells through TGF-β production. Biochem Biophys Res Commun, 415 (3): 526-31. [PMID:22074829]
11. Heiber M, Docherty JM, Shah G, Nguyen T, Cheng R, Heng HH, Marchese A, Tsui LC, Shi X, George SR et al.. (1995) Isolation of three novel human genes encoding G protein-coupled receptors. DNA Cell Biol, 14 (1): 25-35. [PMID:7832990]
12. Huang CW, Tzeng JN, Chen YJ, Tsai WF, Chen CC, Sun WH. (2007) Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors. Mol Cell Neurosci, 36 (2): 195-210. [PMID:17720533]
13. Huang F, Mehta D, Predescu S, Kim KS, Lum H. (2007) A novel lysophospholipid- and pH-sensitive receptor, GPR4, in brain endothelial cells regulates monocyte transmigration. Endothelium, 14 (1): 25-34. [PMID:17364894]
14. Ikeno Y, Konno N, Cheon SH, Bolchi A, Ottonello S, Kitamoto K, Arioka M. (2005) Secretory phospholipases A2 induce neurite outgrowth in PC12 cells through lysophosphatidylcholine generation and activation of G2A receptor. J Biol Chem, 280 (30): 28044-52. [PMID:15927955]
15. Kim KS, Ren J, Jiang Y, Ebrahem Q, Tipps R, Cristina K, Xiao YJ, Qiao J, Taylor KL, Lum H et al.. (2005) GPR4 plays a critical role in endothelial cell function and mediates the effects of sphingosylphosphorylcholine. FASEB J, 19 (7): 819-21. [PMID:15857892]
16. Lardner A. (2001) The effects of extracellular pH on immune function. J Leukoc Biol, 69 (4): 522-30. [PMID:11310837]
17. Lee HY, Shin EH, Bae YS. (2006) Sphingosylphosphorylcholine stimulates human monocyte-derived dendritic cell chemotaxis. Acta Pharmacol Sin, 27 (10): 1359-66. [PMID:17007744]
18. Liu JP, Nakakura T, Tomura H, Tobo M, Mogi C, Wang JQ, He XD, Takano M, Damirin A, Komachi M, Sato K, Okajima F. (2010) Each one of certain histidine residues in G-protein-coupled receptor GPR4 is critical for extracellular proton-induced stimulation of multiple G-protein-signaling pathways. Pharmacol Res, 61 (6): 499-505. [PMID:20211729]
19. Ludwig MG, Vanek M, Guerini D, Gasser JA, Jones CE, Junker U, Hofstetter H, Wolf RM, Seuwen K. (2003) Proton-sensing G-protein-coupled receptors. Nature, 425 (6953): 93-8. [PMID:12955148]
20. Lum H, Qiao J, Walter RJ, Huang F, Subbaiah PV, Kim KS, Holian O. (2003) Inflammatory stress increases receptor for lysophosphatidylcholine in human microvascular endothelial cells. Am J Physiol Heart Circ Physiol, 285 (4): H1786-9. [PMID:12805023]
21. Mahadevan MS, Baird S, Bailly JE, Shutler GG, Sabourin LA, Tsilfidis C, Neville CE, Narang M, Korneluk RG. (1995) Isolation of a novel G protein-coupled receptor (GPR4) localized to chromosome 19q13.3. Genomics, 30 (1): 84-8. [PMID:8595909]
22. Murakami N, Yokomizo T, Okuno T, Shimizu T. (2004) G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine. J Biol Chem, 279 (41): 42484-91. [PMID:15280385]
23. Murata N, Mogi C, Tobo M, Nakakura T, Sato K, Tomura H, Okajima F. (2009) Inhibition of superoxide anion production by extracellular acidification in neutrophils. Cell Immunol, 259 (1): 21-6. [PMID:19539899]
24. No authors listed. (2005) Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the G protein-coupled receptor GPR4. (Retraction). J Biol Chem, 280 (52): 43280. [PMID:16498716]
25. Qiao J, Huang F, Naikawadi RP, Kim KS, Said T, Lum H. (2006) Lysophosphatidylcholine impairs endothelial barrier function through the G protein-coupled receptor GPR4. Am J Physiol Lung Cell Mol Physiol, 291 (1): L91-101. [PMID:16461426]
26. Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON. (2005) Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells. Proc Natl Acad Sci USA, 102 (5): 1632-7. [PMID:15665078]
27. Sanderlin EJ, Leffler NR, Lertpiriyapong K, Cai Q, Hong H, Bakthavatchalu V, Fox JG, Oswald JZ, Justus CR, Krewson EA et al.. (2017) GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis. Biochim Biophys Acta Mol Basis Dis, 1863 (2): 569-584. [PMID:27940273]
28. Seuwen K, Ludwig MG, Wolf RM. (2006) Receptors for protons or lipid messengers or both?. J Recept Signal Transduct Res, 26 (5-6): 599-610. [PMID:17118800]
29. Sin WC, Zhang Y, Zhong W, Adhikarakunnathu S, Powers S, Hoey T, An S, Yang J. (2004) G protein-coupled receptors GPR4 and TDAG8 are oncogenic and overexpressed in human cancers. Oncogene, 23 (37): 6299-303. [PMID:15221007]
30. Sun X, Yang LV, Tiegs BC, Arend LJ, McGraw DW, Penn RB, Petrovic S. (2010) Deletion of the pH sensor GPR4 decreases renal acid excretion. J Am Soc Nephrol, 21 (10): 1745-55. [PMID:20798260]
31. Tobo M, Tomura H, Mogi C, Wang JQ, Liu JP, Komachi M, Damirin A, Kimura T, Murata N, Kurose H, Sato K, Okajima F. (2007) Previously postulated "ligand-independent" signaling of GPR4 is mediated through proton-sensing mechanisms. Cell Signal, 19 (8): 1745-53. [PMID:17462861]
32. Tomura H, Wang JQ, Komachi M, Damirin A, Mogi C, Tobo M, Kon J, Misawa N, Sato K, Okajima F. (2005) Prostaglandin I(2) production and cAMP accumulation in response to acidic extracellular pH through OGR1 in human aortic smooth muscle cells. J Biol Chem, 280 (41): 34458-64. [PMID:16087674]
33. Velcicky J, Miltz W, Oberhauser B, Orain D, Vaupel A, Weigand K, Dawson King J, Littlewood-Evans A, Nash M, Feifel R et al.. (2017) Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis. J Med Chem, 60 (9): 3672-3683. [PMID:28445047]
34. Wang JQ, Kon J, Mogi C, Tobo M, Damirin A, Sato K, Komachi M, Malchinkhuu E, Murata N, Kimura T, Kuwabara A, Wakamatsu K, Koizumi H, Uede T, Tsujimoto G, Kurose H, Sato T, Harada A, Misawa N, Tomura H, Okajima F. (2004) TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. J Biol Chem, 279 (44): 45626-33. [PMID:15326175]
35. Wang Y, de Vallière C, Imenez Silva PH, Leonardi I, Gruber S, Gerstgrasser A, Melhem H, Weber A, Leucht K, Wolfram L et al.. (2018) The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation. J Crohns Colitis, 12 (3): 355-368. [PMID:29136128]
36. Wyder L, Suply T, Ricoux B, Billy E, Schnell C, Baumgarten BU, Maira SM, Koelbing C, Ferretti M, Kinzel B et al.. (2011) Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor. Angiogenesis, 14 (4): 533-44. [PMID:22045552]
37. Yang LV, Radu CG, Roy M, Lee S, McLaughlin J, Teitell MA, Iruela-Arispe ML, Witte ON. (2007) Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor. Mol Cell Biol, 27 (4): 1334-47. [PMID:17145776]
38. Zhu K, Baudhuin LM, Hong G, Williams FS, Cristina KL, Kabarowski JH, Witte ON, Xu Y. (2001) Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the G protein-coupled receptor GPR4. J Biol Chem, 276 (44): 41325-35. [PMID:11535583]
target has curated data in GtoImmuPdb
