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GPR12

Family: Class A Orphans

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 334 13q12 GPR12 G protein-coupled receptor 12 8
Mouse 7 334 5 G3 Gpr12 G-protein coupled receptor 12 7
Rat 7 334 12p11 Gpr12 G protein-coupled receptor 12
Previous and Unofficial Names
GPCR21
MGC156481
Gpcr12
Gpcr01
Gpcr20
GPR12
G-protein coupled receptor 12
GPCR12
R334
Database Links
ChEMBL Target 101258 (Hs)
Ensembl ENSG00000132975 (Hs), ENSMUSG00000041468 (Mm), ENSRNOG00000039832 (Rn)
Entrez Gene 2835 (Hs), 14738 (Mm), 80840 (Rn)
GeneCards GPR12 (Hs)
GenitoUrinary Development Molecular Anatomy Project Gpr12 (Mm)
HomoloGene 3868 (Hs)
Human Protein Reference Database 15978 (Hs)
InterPro P47775 (Hs), P35412 (Mm), P30951 (Rn)
KEGG Gene hsa:2835 (Hs), mmu:14738 (Mm), rno:80840 (Rn)
OMIM 600752 (Hs)
PharmGKB Gene PA28856 (Hs)
PhosphoSitePlus P47775 (Hs), P35412 (Mm), P30951 (Rn)
Protein Ontology (PRO) PRO:000001636 (Hs)
RefSeq Nucleotide NM_005288 (Hs), NM_008151 (Mm), NM_030831 (Rn)
RefSeq Protein NP_005279 (Hs), NP_032177 (Mm), NP_110458 (Rn)
TreeFam ENSG00000132975 (Hs), ENSMUSG00000041468 (Mm), ENSRNOG00000039832 (Rn)
UniGene Hs. 123034 (Hs)
UniProt P47775 (Hs), P35412 (Mm), P30951 (Rn)
Wikipedia GPR12
Orphan and other 7TM receptors
Natural/Endogenous Ligand(s)
sphingosine 1-phosphate
Comments: Proposed ligand, single publication
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
sphingosyl phosphorylcholine Hs Full agonist 7.18 – 7.49 pEC50 4
sphingosine 1-phosphate Hs Full agonist 6.97 pEC50 10
sphingosine 1-phosphate Hs Full agonist 5.51 – 5.92 pEC50 10
Agonist Comments
Proposed ligand (sphingosine 1-phosphate), supported by one publication [10]. However, this was not repeated in a later study using the β-arrestin PathHunter assay [11]. EC50 values were obtained by two assays analysing the effect of ligands on K+ current and Ca2+ luminescene respectively [4]. Tyrosol has been proposed to be a possible ligand for GPR12 [5]. Uhlenbrock et al. show that the agonist efficacy of GPR12 was increased in the presence of suramin [10]. They also found out that EC50 value of gpr12 to dihydrosphingosine 1-phosphate was in the similar range as that of sphingosine-1-phospate.
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family
Gi/Go family 		Adenylate cyclase stimulation
Adenylate cyclase inhibition
References:  4,6,9-10
Tissue Distribution
Vascular smooth muscle cells of aorta, coronary artery and pulmonary artery, microvascular endothelual cells of the lung, pulmonary artery, coronary artery and umbilical vein
Species:  Human
Technique:  RT-PCR
References:  10
Primary endothelial cells of pulmonary artery, coronary artery, iliac artery, aortic artery, lung microvasculature, umbilical vein, umbilical artery and dermal microvasculature. Primary vascular smooth muscle cells of aorta, bronchi, coronary artery, pulmonary artery, umbilical artery, uterus and skeletal muscle.
Species:  Human
Technique:  Western Blot
References:  10
Ovary. GPR3 RNA was not detected in human oocyte.
Species:  Human
Technique:  RT-PCR
References:  2
Embyronal brain: Cortical plate, piriform cortex, hippocampus, dorsomedial and arcuate nuclei, motoric and sensoric nuclei of the hindbrain in the medullary reticular formation, caudate putamen, mammilary body
Species:  Mouse
Technique:  in situ hybridisation
References:  4
Mature brain: somatosensory and retrosplenial complex, hippocampus with the highest expression in the pyramidal cells of CA2 region, nucleus accumbens, piriform cortex, septum, the mitral and glomerular cell layers of the olfactory bulb, amygdala, geniculate nucleus. No gpr12 expression was detected in fiber tracts in the corpus callosum.
Species:  Mouse
Technique:  in situ hybridisation
References:  4
Highest expression in brain. A signicant amount of GPR12 transcript was detected in liver.
Species:  Mouse
Technique:  RT-PCR
References:  9
Medial habenular nucleus, cerebral cortex, hippocampus, olfactory bulb, striatum
Species:  Mouse
Technique:  in situ hybridisation
References:  7
Limbic system: dentate gyrus, indusium griseum, fasciola cinereum, posteromedial cortical amygdala nucleus, anterior cingulate cortex, retrosplenial granular cortex, prelimbic cortex
Species:  Mouse
Technique:  Lac Z staining of Gpr12 KO mouse brain
References:  1
Oocytes
Species:  Mouse
Technique:  RT-PCR
References:  3
Forebrain, hindbrain, testis
Species:  Mouse
Technique:  Northern blot
References:  7
Oocytes
Species:  Rat
Technique:  RT-PCR and in situ hybridisation.
References:  3
Tissue Distribution Comments
Higher expresssion of GPR12 was detected in areas of neuronal differentiation, whereas GPR12 transcritpts were not detected in the regions of neuroblast proliferation [4]. GPR12 protein expression was upregulated in human vascular endothelial cells exposed to fluid shear stress, despite that there was no increase of GPR12 expression in the mRNA level [10]. GPR12 RNA was not detected in human oocytes examined by RT-PCR [2].
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
Inhibition of RhoA activation through PKA activation
Species:  Rat
Tissue:  Cerebellar granule neuron
Response measured: 
References:  9
Physiological Functions
Involved in sphingosylphosphorycholine-induced cell proliferation.
Species:  Mouse
Tissue:  Hippocampus
References:  4
Stimulate synaptophysin production
Species:  Rat
Tissue:  Neuron
References:  9
Involved in meiotic arrest in rat oocytes.
Species:  Rat
Tissue:  Oocytes
References:  3,6,12
Physiological Consequences of Altering Gene Expression
Oocyte maturation. Rat oocytes with Gpr12 knockdown undergo meiotic resumption.
Species:  Rat
Tissue:  Oocytes
Technique:  RNA interference
References:  3-4
Mice with Gpr12 knockout have higher body weight and body fat mass, lower respiratory exchange ratio, lower energy expenditure, hepatic steatosis and are dyslipidermic.
Species:  Mouse
Tissue:  Limbic and sensory systems
Technique:  Gene Knockout
References:  1
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0005278 abnormal cholesterol homeostasis PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0005450 abnormal energy expenditure PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0010379 decreased respiratory quotient PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0001260 increased body weight PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0005178 increased circulating cholesterol level PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0005559 increased circulating glucose level PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0001556 increased circulating HDL cholesterol level PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0000182 increased circulating LDL cholesterol level PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0009285 increased gonadal fat pad weight PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0009355 increased liver triglyceride level PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0002981 increased liver weight PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0005458 increased percent body fat PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0009304 increased retroperitoneal fat pad weight PMID: 16887097 
Gpr12tm1Dgen Gpr12tm1Dgen/Gpr12tm1Dgen
B6.129P2-Gpr12		 MGI:101909  MP:0001261 obese PMID: 16887097 
General Comments
GPR12 is a potential target for treating some neurological disorders, including brain and spinal injuries, stroke, and neurogenerative disorders [9].
Available Assays
DiscoveRx PathHunter® CHO-K1 GPR12 (Orphan) High Expression β-Arrestin Cell Line Human Cat No. 93-0329C2A

REFERENCES

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1. Bjursell, M; Gerdin, AK; Jönsson, M; Surve, VV; Svensson, L; Huang, XF; Törnell, J; Bohlooly-Y, M. (2006) G protein-coupled receptor 12 deficiency results in dyslipidemia and obesity in mice. Biochem. Biophys. Res. Commun., 348 (2): 359-66. [PMID:16887097]

2. DiLuigi, A; Weitzman, VN; Pace, MC; Siano, LJ; Maier, D; Mehlmann, LM. (2008) Meiotic arrest in human oocytes is maintained by a Gs signaling pathway. Biol. Reprod., 78 (4): 667-72. [PMID:18184921]

3. Hinckley, M; Vaccari, S; Horner, K; Chen, R; Conti, M. (2005) The G-protein-coupled receptors GPR3 and GPR12 are involved in cAMP signaling and maintenance of meiotic arrest in rodent oocytes. Dev. Biol., 287 (2): 249-61. [PMID:16229830]

4. Ignatov, A; Lintzel, J; Hermans-Borgmeyer, I; Kreienkamp, HJ; Joost, P; Thomsen, S; Methner, A; Schaller, HC. (2003) Role of the G-protein-coupled receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its expression and function in brain development. J. Neurosci., 23 (3): 907-14. [PMID:12574419]

5. Lin, ZJ; Lu, XM; Zhu, TJ; Fang, YC; Gu, QQ; Zhu, W. (2008) GPR12 selections of the metabolites from an endophytic Streptomyces sp. associated with Cistanches deserticola. Arch. Pharm. Res., 31 (9): 1108-14. [PMID:18806952]

6. Meyer zu Heringdorf, D; Jakobs, KH. (2007) Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim. Biophys. Acta, 1768 (4): 923-40. [PMID:17078925]

7. Saeki, Y; Ueno, S; Mizuno, R; Nishimura, T; Fujimura, H; Nagai, Y; Yanagihara, T. (1993) Molecular cloning of a novel putative G protein-coupled receptor (GPCR21) which is expressed predominantly in mouse central nervous system. FEBS Lett., 336 (2): 317-22. [PMID:8262253]

8. Song, ZH; Modi, W; Bonner, TI. (1995) Molecular cloning and chromosomal localization of human genes encoding three closely related G protein-coupled receptors. Genomics, 28 (2): 347-9. [PMID:8530049]

9. Tanaka, S; Ishii, K; Kasai, K; Yoon, SO; Saeki, Y. (2007) Neural expression of G protein-coupled receptors GPR3, GPR6, and GPR12 up-regulates cyclic AMP levels and promotes neurite outgrowth. J. Biol. Chem., 282 (14): 10506-15. [PMID:17284443]

10. Uhlenbrock, K., Gassenhuber, H. and Kostenis, E. (2002) Sphingosine 1-phosphate is a ligand of the human gpr3, gpr6 and gpr12 family of constitutively active G protein-coupled receptors. Cell Signal, 14: 941-953. [PMID:12220620]

11. Yin, H., Chu, A., Li, W., Wang, B., Shelton, F., Otero, F., Nguyen, D.G., Caldwell, J.S. and Chen, Y.A. (2009) Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem, 284: 12328-12338. [PMID:19286662]

12. Zhang, M; Xia, G. (2012) Hormonal control of mammalian oocyte meiosis at diplotene stage. Cell. Mol. Life Sci., 69 (8): 1279-88. [PMID:22045555]

To cite this database page, please use the following:

Wen Chiy Liew.
Class A Orphans: GPR12. Last modified on 05/09/2012. Accessed on 19/06/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=86.


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