<i>GPR4</i> | Class A Orphans | IUPHAR/BPS Guide to PHARMACOLOGY

GPR4

Target id: 84

Nomenclature: GPR4

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for GPR4 in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 362 19q13.3 GPR4 G protein-coupled receptor 4 9,18
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
Specialist databases
GPCRDB gpr4_human (Hs), gpr4_mouse (Mm), gpr4_rat (Rn)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
Protons
Comments: The role of GPR4 as a proton-sensing receptor is supported by several publications.
Agonist Comments
A report that sphingosylphosphorylcholine (SPC) and lysophosphatidylcholine (LPC) were ligands for GPR4 [32] was subsequently retracted [21]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [6,24].
Antagonist Comments
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 [29]. This effect is seen with other proton-sensing receptors.
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family
Gi/Go family
Gq/G11 family
G12/G13 family
Adenylate cyclase stimulation
Phospholipase C stimulation
Comments:  Coupling to Gs-induced cAMP formation following activation by protons [15-16,27].

Coupling to the G12/13/Rho signalling pathway and the Gq/PLC signalling pathway have also been reported [15].

Histidine residues at positions 79, 165 and 269 are important for the receptor's coupling to multiple signalling pathways [15].
References:  25
Tissue Distribution
Endothelial cells (high levels); smooth muscle cells, skeletal muscle, skin fibroblasts, lung fibroblasts, colon epithelial cells and renal epithelial cells (low levels)
Species:  Human
Technique:  Extended DNA microarray analysis
References:  30
Kidney, heart and lung
Expression level:  High
Species:  Human
Technique:  Northern blot
References:  18
Endothelial cells from brain and skin
Species:  Human
Technique:  RT-PCR
References:  17
Kidney, colon and ovarian tumours (high), liver (low)
Species:  Human
Technique:  RT-PCR
References:  25
Thyroid cells and thyroid cancer cells, brain
Species:  Human
Technique:  RT-PCR
References:  1
Brain microvascular endothelial cells
Species:  Human
Technique:  Western blot
References:  22
Human brain microvascular endothelial cells (HBMECs) and human dermal microvascular endothelial cells (HMECs)
Species:  Human
Technique:  Western blot, immunofluorescent localisation
References:  11
Aortic smooth muscle cells
Species:  Human
Technique:  RT-PCR
References:  28
Brain
Species:  Mouse
Technique:  RT-PCR
References:  12
Kidney (cortex, outer medulla, inner medulla thick ascending limbs)
Species:  Mouse
Technique:  RT-PCR
References:  26
Bone
Species:  Mouse
Technique:  RT-PCR
References:  7
Brain (cerebrum, brain stem, cerebellum), spinal chord, dorsal root ganglion, trigeminal ganglion, skeletal muscle, lung
Species:  Mouse
Technique:  RT-PCR
References:  10
Tissue Distribution Comments
Northern blot analysis failed to detect GPR4 in the putamen, pons, frontal cortex, hypothalamus, hippocampus, thalamus or cerebellum [9]. Not detected by RT-PCR in MG63 human osteosarcoma cells [16]. RT-PCR analysis showed that GPR4 is not expressed on mature or immature human monocytes [14]. Not detected in human neutrophils by RT-PCR [20].

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 [17]. 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 [23].

The expression of GPR4 in dorsal root ganglion neurons suggests a role for the receptor in nociception [10].
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Knockout of ASIC-3 induced increased expression of GPR4 in trigeminal ganglion
Species:  Mouse
Tissue:  Trigeminal ganglion
Response measured:  GPR4 expression
References:  10
GPR4 expression reduced activation of ERK induced by GPCR and EGF receptor tyrosine kinase signalling
Species:  Human
Tissue:  HEK 293 cells
Response measured:  Activation of ERK
References:  2
Stimulation of HBMEC cells with TNF-alpha increased GPR4 expression, detected by RT-PCR
Species:  Human
Tissue:  HBMEC cells
Response measured:  GPR4 expression
References:  17
Measurement of the activation of cAMP formation in transiently-transfected HEK293 cells showed that half-maximal activation occurs at pH 7.55. Stimulation of cAMP formation was not pH dependent in untransfected cells.
Species:  Human
Tissue:  HEK 293 cells
Response measured:  cAMP formation
References:  16
Activation of GPR4 by acid pH increased cell adhesion of HUVEC cells. This effect was reduced following downregulation of GPR4 expression by RNA interference
Species:  Human
Tissue:  Human umbilical vein endothelial cells (HUVEC)
Response measured:  Cell adhesion
References:  4
cAMP-production, although described as pH-dependent was found to be higher in GPR4-expressing cells even at alkaline pHs than in controls.
Species:  None
Tissue:  HEK 293T (293T) cells
Response measured:  cAMP production
References:  23
Overexpression of GPR4 in NIH3T3 cells induced cellular changes characteristic of oncogenic transformation. These included refractile cell shape, foci formation and tolerance to low serum condition in vitro. Retrovirus-infected stable NIH3T3 cells were injected into athymic nude mice. All mice injected with GPR4-transformed cells developed tumours within 6 weeks.
Species:  Mouse
Tissue:  NIH3T3 cells transfected with GPR4
Response measured:  Tumour development
References:  25
siRNA experiments demonstrated that GPR4 plays a critical role in tube formation in HUVEC and HMEC-1 cells
Species:  Human
Tissue:  Endothelial cells
Response measured:  Tube formation
References:  13
Exposure of HUVECs to mild extracellular acidosis induced slightly increased cAMP production. This response was amplified by the addition of forskolin which activates adenylyl cyclases in synergy with GαS. This pH-dependent cAMP increase was prevented by the use of siRNA-transfected HUVECs prior to extracellular acidosis
Species:  Human
Tissue:  Primary human umbilical vein endothelial cells (HUVECs)
Response measured:  cAMP production
References:  30
GPR4 activation by an acidic pH inhibits tumor cell migration and invasion
Species:  Mouse
Tissue:  B16F10 melanoma cells and TRAMP-C1 prostate cancer cells
Response measured:  RhoA-GTPase activation and actin stress fibre formation
References:  3
Adenylyl cyclase activity increases as pH decreases in a medium prepared from RH7777 cells. In an additional assay the authors confirmed earlier findings of Bektas et al. that EGR-induced ERK activation is lower in GPR4-transfected cells than controls at a physiological pH of 7.4. As this difference is not as clear at pH 7.8, the authors demonstrated that EGF-induced ERK activation is dependent on extracellular pH and GPR4 acts as a proton sensor
Species:  Rat
Tissue:  RH7777 cells transfected with GPR4
Response measured:  Adenylyl cyclase activity
References:  27
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 [29].
Physiological Functions
GPR4 is critical for tube formation in microvascular endothelial cells
Species:  Human
Tissue:  Endothelial cells
References:  13
Acidosis and GPR4 signalling regulate endothelial cell adhesion via the Gs/cAMP/EPAC pathway. This may play a role in the inflammatory response of vascular endothelial cells
Species:  Human
Tissue:  Human umbilical vein endothelial cells (HUVECs)
References:  4
Physiological Consequences of Altering Gene Expression
Overexpression of GPR4 in HEK-293 cells increased both basal and acid-stimulated protein kinase A activity. The same study found that GPR4-expressing cells express higher levels of HKα2 (H+-K+-ATPase α-subunit than do vector-transfected control cells
Species:  Human
Tissue:  HEK-293 cells
Technique:  Immunoblot assay
References:  5
Use of siRNA in HUVEC demonstrated that GPR4 is critical for the angiogenesis, proliferation and migration of endothelial cells induced by SPC
Species:  Human
Tissue:  Human umbilical vein endothelial cells (HUVEC)
Technique:  siRNA
References:  13
siRNA and antibody-mediated knockdown of GPR4 in nTregs shows that expression levels of TGF-β1 mRNA increased to similar levels to control nTregs following stimulation with LPC, indicating that LPC does not enhance expression of TGF-β1 through GPR4
Species:  Human
Tissue:  Naturally occurring CD4+CD25+ regulatory T cells (nTregs)
Technique:  RNA interference, and anti-GPR4 polyclonal antibodies
References:  8
GPR4 knockout mice show reduced tumour growth owing to a reduced angiogenic response to VEGF but not to bFGF (basic fibroblast growth factor). A growth factor implant model was used. The same study showed that GPR4 knockout mice are viable and fertile with no signficant histopathological differences evident when compared to wild-type. A second model usuing CT26 colon tumour cells showed reduced tumour growth in GPR4 deficient mice than in wild-type controls.
Species:  Mouse
Tissue:  c CT26 colon tumor cells
Technique:  Gene knockouts
References:  30
siRNA- mediated knockout of GPR4 inhibits LPC-stimulated monocyte transmigration. This effect could be reversed by a GPR4 construct resistant to siRNA. LPC-induced RhoA-activation was also inhibited by siRNA
Species:  Human
Tissue:  HBMEC cells
Technique:  RNA interference (RNAi)
References:  11
GPR4 knockout mice exhibit metabolic acidosis, with lower blood PCO2 in compensation when compared to wildtype controls. The knockout phenotype also displayed higher blood chloride and more alkaline urine. Pronounced hypercalcaemia in the knockout mice; this is associated with metabolic acidosis.
Species:  Mouse
Tissue:  Kidney
Technique:  Gene knockouts
References:  26
Acid-induced cAMP accumulation was slightly inhibited in aortic smooth muscle cells when GPR4 expression was inhibited by siRNA
Species:  Human
Tissue:  Aortic smooth muscle cells
Technique:  siRNA
References:  28
Increased perinatal lethality in GPR4 deficient mice with hemorrhage seen in some of the deficient mice, and respiratory distress in others
Species:  Mouse
Tissue: 
Technique:  Homologous recombination
References:  31
Deletion of GPR4 decreased net acid secretion by the kidney and resulted in a nongap metabolic acidosis, indicating that GPR4 is required to maintain acid-base homeostasis.
Species:  Mouse
Tissue:  Kidney
Technique:  Homologous recombination
References:  26
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 [26].

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].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0000260 abnormal angiogenesis PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0001614 abnormal blood vessel morphology PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0005327 abnormal mesangial cell PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0005325 abnormal renal glomerulus morphology PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0005592 abnormal vascular smooth muscle morphology PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0005488 bronchial epithelial hyperplasia PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0001575 cyanosis PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0005435 hemoperitoneum PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0001914 hemorrhage PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0000533 kidney hemorrhage PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0001182 lung hemorrhage PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0002058 neonatal lethality PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0002082 postnatal lethality PMID: 17145776 
Gpr4tm1Witt Gpr4tm1Witt/Gpr4tm1Witt
either: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)
MGI:2441992  MP:0001954 respiratory distress PMID: 17145776 
Biologically Significant Variants
Type:  Naturally occurring SNP
Species:  Human
Amino acid change:  S295N
Nucleotide change:  G>A
Comment on frequency:  Low frequency (<10% of all tested populations)
SNP accession: 
Type:  Naturally occurring SNP
Species:  Human
Amino acid change:  T133P
SNP accession: 
General Comments
The role of GPR4 as a proton-sensing receptor is supported by several publications [6,24].

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 [25]. There is an overlapping expression pattern between the members of this GPCR subfamily [25].

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 [19]. 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 [16].

References

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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. 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]

8. 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]

9. Heiber M, Docherty JM, Shah G, Nguyen T, Cheng R, Heng HH, Marchese A, Tsui LC, Shi X, George SR. (1995) Isolation of three novel human genes encoding G protein-coupled receptors. DNA Cell Biol, 14: 25-35. [PMID:7832990]

10. 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]

11. 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]

12. 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]

13. 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]

14. Lee HY, Shin EH, Bae YS. (2006) Sphingosylphosphorylcholine stimulates human monocyte-derived dendritic cell chemotaxis. Acta Pharmacol. Sin., 27 (10): 1359-66. [PMID:17007744]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. 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. U.S.A., 102 (5): 1632-7. [PMID:15665078]

24. 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]

25. 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]

26. 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]

27. 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]

28. 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]

29. 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]

30. 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]

31. 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]

32. 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]

Contributors

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How to cite this page

Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: GPR4. Last modified on 30/07/2015. Accessed on 15/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=84.