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GPR4

Family: Class A Orphans

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
Biologically Significant Variants
General Comments
References
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
MGC116369
GPR4
G-protein coupled receptor 4
G-protein coupled receptor 19
GPR19
Gpr4_predicted
LOC308408
G protein-coupled receptor 4
G protein-coupled receptor 4 (predicted)
Database Links
Ensembl ENSG00000177464 (Hs), ENSMUSG00000044317 (Mm), ENSRNOG00000016362 (Rn)
Entrez Gene 2828 (Hs), 319197 (Mm), 308408 (Rn)
GeneCards GPR4 (Hs)
GenitoUrinary Development Molecular Anatomy Project Gpr4 (Mm)
HomoloGene 3867 (Hs)
Human Protein Reference Database 02773 (Hs)
InterPro P46093 (Hs), Q8BUD0 (Mm), Q4KLH9 (Rn)
KEGG Gene hsa:2828 (Hs), mmu:319197 (Mm), rno:308408 (Rn)
OMIM 600551 (Hs)
PharmGKB Gene PA28886 (Hs)
PhosphoSitePlus P46093 (Hs), Q8BUD0 (Mm), Q4KLH9 (Rn)
Protein Ontology (PRO) PRO:000001644 (Hs)
RefSeq Nucleotide NM_005282 (Hs), NM_175668 (Mm), NM_001025680 (Rn)
RefSeq Protein NP_005273 (Hs), NP_783599 (Mm), NP_001020851 (Rn)
TreeFam ENSG00000177464 (Hs), ENSMUSG00000044317 (Mm), ENSRNOG00000016362 (Rn)
UniGene Hs. 17170 (Hs)
UniProt P46093 (Hs), Q8BUD0 (Mm), Q4KLH9 (Rn)
Wikipedia GPR4
Orphan and other 7TM receptors
Natural/Endogenous Ligand(s)
(lyso)phospholipid mediators, protons
Comments: Lysophospholipids are proposed ligands, publication since retracted. The role of GPR4 as a proton-sensing receptor is supported by several publications.
Agonist Comments
A study showing sphingosylphosphorylcholine (SPC) and lysophosphatidylcholine (LPC) to be ligands fo GPR4 has since been withdrawn [38]. This results were also shown in a second study which also tested psychosine as an antagonist for GPR4 [33].

There remains controversy over the role of GPR4 as a receptor for SPC and LPC [30]; however, it is now accepted to be a proton-sensing receptor, originally proposed by Ludwig et al., 2003 [16]. Bektas et al. showed inability of GPR4 to respond to the proposed lysophospholipid agonists using a several assay systems [3]. Both of these lysophospholid ligands increase during inflammatory stress, therefore the receptor was believed to play a role in the response to inflammation. It has been suggested that if GPR4 does act as a receptor for one or more lysophospholipids in addition to protons then this diversity in agonists is indicative that it may function as an integration point for extracellular stimuli [1]. Results supporting a role as an SPC receptor show that GPR4 activation attentuates cell proliferation which would support a possible role in oncogenesis [13]. While the papers proposing LPC and SPC to be ligands for GPR4 have been retracted, SPC is still proposed to be a ligand for GPR4 when expressed in vascular endothelial cells [13,24]. The results of Zou et al. suggest that adhesion molecule upregulation is a YPEN-1 cell assay is induced by LPC-stimulation of GPR4 although these results have not been repeated [39].

TDAG8 receptor agonist BTB09089 has been shown to not be a ligand for GPR4 [22].
Antagonist Comments
In an assay measuring cAMP accumulation in GPR4-transfected CHO cells, psychosine was shown to competivitely inhibit the cAMP acculmulation induced by proton-stimulation of GPR4 [31]. 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 folowing activation by protons [16]. The use of mulitple signal transduction pathways by this receptor may contribute to its tumorigenicity through elevated SRE- and CRE-driven transcription [26]. Ludwig et al. found that activation of second messanger pathways is not dependent on activation of the receptor by proposed agonists SPC and LPC [16]. These results are supported by the findings of Bektas et al. who showed that GPR4 signalling is ligand-independent [3].

GPR4 is coupled to the G12/13/Rho signalling pathway [29], the Gq/PLC signalling pathway and the Gs/cAMP signalling pathway [15].

Histidine residues at positions 79, 165 and 269 are important for the receptor's coupling to multiple signalling pathways [15].

The results of Tobo et al. show that GPR4 when stimulated by extracellular protons activated the Gs-protein/adenylyl cyclase/cAMP system which is believed to be involved in ERK inhibition [29].
References:  26
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:  32
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:  26
Aortic smooth muscle cells
Species:  Human
Technique:  RT-PCR
References:  30
Thyroid cells and thyroid cancer cells, brain
Species:  Human
Technique:  RT-PCR
References:  1
Brain microvascular endothelial cells
Species:  Human
Technique:  Western blot
References:  24
Human brain microvascular endothelial cells (HBMECs) and human dermal microvascular endothelial cells (HMECs)
Species:  Human
Technique:  Western blot, immunofluorescent localisation
References:  11
Brain
Species:  Mouse
Technique:  RT-PCR
References:  12
Bone
Species:  Mouse
Technique:  RT-PCR
References:  7
Kidney (cortex, outer medulla, inner medulla thick ascending limbs)
Species:  Mouse
Technique:  RT-PCR
References:  28
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 traces of GPR4 in the putamen, pons, frontal cortex, hypothalamus, hippocampus, thalamus and cerebellum [9]. Not detected by RT-PCT 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 [21].

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 [25].

Cell line analysis by RT-PCR showed that GPR4 was not expressed in a U937 cell line [36]. RT-PCR also showed GPR4 was not expressed in PC12 cells. Weak expression in a THP-1 cell line with RT-PCR analysis [23]. YPEN-1 cells expressed GPR4 when analysed by RT-PCR [39].

The expression of GPR4 on the nociceptors of dorsal root ganglion 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
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
Knockout of ASIC-3 induced increased expression of GPR4 in trigeminal ganglion suggesting a role of compensation in acid-sensing
Species:  Mouse
Tissue:  Trigeminal ganglion
Response measured:  GPR4 expression
References:  10
Proposed lysophospholipid agonists SPC and LPC were not found to induce internalization of GPR4 from the plasma membrane. Additionally, these phospholipids do not induce translocation of β-arrestin2-GRP from the cytosol to the plasma membrane in GPR4 expressing cells.
Species:  Human
Tissue:  HEK 293 cells
Response measured:  GPR4 internalisation; translocation of βarrestin 2
References:  3
Measurement of the activation of cAMP 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
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:  3
siRNA knockdown of Gα13 inhibits pH-induced SRE activation, along with Gα13 mRNA expression in GPR4. The siRNA treatment did not significantly effect the pH-dependent cAMP accumulation. These results suggest that GPR4 is coupled to G13 proteins and the Rho signalling pathway through p115RhoGEF, leading to SRE activation, in addition to the Gs mediated activation of adenylyl cyclase/cAMP also induced by extracellular protons
Species:  Human
Tissue:  GPR4-expressing cells
Response measured:  SRE activation
References:  29
When overexpressed in tumour cells lines, GPR4 induced stress fiber formation and RhoA-GTPase activation following stimulaion by acidosis. This acidosis stimulation supressed the invasion of the cells through the extracellualr matrix and an endothelial cells layer
Species:  Mouse
Tissue:  B16F10 melanoma cells and TRAMP-C1 prostate cancer cells
Response measured:  RhoA-GTPase activation and actin stress fibre formation
References:  4
Isocapnic acidosis activation of GPR4 increases cell adhesion of HUVEC cells. This effect is reduced with RNA interference downregulation of GPR4 expression
Species:  Human
Tissue:  Human umbilical vein endothelial cells (HUVEC)
Response measured:  Cell adhesion
References:  5
cAMP-production, although described as pH-dependent was found to be higher in GPR4-expressing cells even at alkaline pHs than in controls. Shown by use of a 293T overexpression system
Species:  None
Tissue:  HEK 293T (293T) cells
Response measured:  cAMP production
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
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
Response measured:  Adenylyl cyclase activity
References:  29
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
Response measured:  Tumour development
References:  26
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:  32
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 [31].
Physiological Functions
GPR4 is critical for tube formation in microvascular endothelial cells
Species:  Human
Tissue:  Endothelial cells
References:  13
Regulation of pH homeostasis in the kidney
Species:  Mouse
Tissue:  Kidney
References:  28
GPR4 is implicated in playing a role in the integrity of the endothelial barrier; barrier-dysfuction response is GPR4-dependent. Tested using resistance electrodes
Species:  Human
Tissue:  Endothelial barrier
References:  24
Mediation of the proliferation, migration and tube formation effects of sphingosylphosphorylcholine
Species:  Mouse
Tissue: 
References:  27
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:  5
Physiological Consequences of Altering Gene Expression
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:  28
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:  30
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:  6
Increased perinatal lethality in GPR4 deficient mice with hemorrhaging seen in some of the deficient mice, and respiratory distress in others
Species:  Mouse
Tissue: 
Technique:  Homologous recombination
References:  35
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:  32
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
Physiological Consequences of Altering Gene Expression Comments
The findings of Huang et al. support the view that GPR4 is an LPC-sensing receptor in addition to its role in proton sensing. They also state that GPR4 may be more sensitive to LPC than to changes in the extracellular pH [11]. As GPR4 activation through the effects of RhoA, these findings also support the view that GPR4 stimulates several signal transduction pathways.

Knockout experiments in mice resulting in metabolic acidosis from impaired kidney function implicate GPR4 as having an important role as a proton-sensing receptor in the kidney [28].

Codina et al. speculate that pH-activated GPR4 plays a regulatory role in the homeostatic regulation of HKα2 and the acid-base balance, by means of increasing HKα2 via increased PKA activity [6].
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 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Muscular dystrophy
References:  18
Mutations not determined
Disease:  Cancer
Comments:  There is a potential role for GPR4 in the pathology of thyroid cancer
References:  1,26
Mutations not determined
Gene Expression and Pathophysiology Comments
OLETF rats exhibited increased aortic GPR4 mRNA expression when compared to age-matched controls, detected by RT-PCR [19].
Biologically Significant Variants
T133P
SNP accession:  rs77868669 
Type:  Naturally occurring SNPs.
Species:  Human
References: 
A120G
SNP accession:  rs79625825 
Type:  Naturally occurring SNPs.
Species:  Human
References: 
A G->A missense nucleotide change causes amino acid substitution S295N, with low frequency (<10% of all tested populations)
SNP accession:  rs36012326 
Type:  Naturally occurring SNPs.
Species:  Human
References: 
General Comments
GPR4 has a high sequence similarity with GPR6C.1 [2]. GPR4 has been shown to be closely related to the platelet activating receptor (PAF) [9]. Two isoforms of GPR4 are expressed in humans [18]. A high degree of sequence similarity is also seen with GPR68 [3,34] and GPR132 [20]. Several studies state that GPR4 is a member of a GPCR orphan receptor subfamily consisting of OGR1 (ovarian cancer G protein-coupled receptor 1, TDAG8 and G2A [3,12] and that these receptors are an emerging class of ongogenic GPCRs [26]. There is an overlapping expression pattern between the members of this GPCR subfamily [26].

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 [20]. The structural features essential for acid induction of inositol phosphate formation displayed by OCR1 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.

GPR4 elicits formation of cyclic AMP [16].

The wide expression pattern of GPR4 suggests its function as an acid-sensing receptor is involved in a wider range of physiological process than the specific acid-sensing ion channels with an established role in nociception [16].

It is anticipated that GPR4 and its closely related receptors will form targets for the development of new anti-cancer small molecule drugs [26]. This study also speculates that the proton-sensing role of GPR4 may also given tumour cells with GPR4 over-expression a survival advantage in surviving acidic environments.

GPR4 forms homo- and hetero-dimers with LPA and S1P receptors [37].
Available Assays
DiscoveRx PathHunter® CHO-K1 GPR4 (Orphan) High Expression β-Arrestin Cell Line Human Cat No. 93-0369C2A

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. An, S; Tsai, C; Goetzl, EJ. (1995) Cloning, sequencing and tissue distribution of two related G protein-coupled receptor candidates expressed prominently in human lung tissue. FEBS Lett., 375 (1-2): 121-4. [PMID:7498459]

3. 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]

4. 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]

5. 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]

6. 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]

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, J. M., Shah, G., Nguyen, T., Cheng, R., Heng, H. H., Marchese, A., Tsui, L. C., Shi, X. and George, S. R. (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]

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To cite this database page, please use the following:

Helen E. Benson.
Class A Orphans: GPR4. Last modified on 02/11/2012. Accessed on 25/05/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=84.


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