| G protein-coupled receptor 3 | OKDB#: 1407 |
| Symbols: | GPR3 | Species: | human | ||
| Synonyms: | ACCA,ACCA, ADENYLATE CYCLASE CONSTITUTIVE ACTIVATOR, ACCA| | Locus: | 1p36.1-p35 in Homo sapiens | HPMR |
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| General Comment |
Identification of a novel small molecule agonist for human GPR3. Ye C 2014 et al.
GPR3 is an orphan G protein-coupled receptor (GPCR) predominantly expressed in mammalian brain and oocytes. GPR3 plays important roles in these two organs and is known as a Gas-coupled receptor activated constitutively in cells. However, the signal transduction pathway and pharmacological function of GPR3 remain unclear due to the lack of a specific ligand. Using a HEK293 cell line stably expressing flag-GPR3-GFP, a chemical screening for GPR3 ligands was performed using homogeneous time resolved fluorescence (HTRF) cAMP assay. Diphenyleneiodonium chloride (DPI) was identified as a novel agonist of GPR3 with weak or no cross-reactivity with other GPCRs. DPI was further characterized to activate several GPR3-mediated signal transduction pathways, including calsium mobilization, cAMP accumulation, ERK activation, membrane recruitment of -arrestin2 and receptor desensitization. Parallel studies revealed that the activity of DPI is much more pronounced than S1P, a previously reported GPR3 agonist. Our study identified a novel and specific agonist of GPR3, which provides a useful tool for further study of this orphan GPCR.
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Eggerickx D, reported the molecular cloning of a G-protein-coupled receptor that
constitutively activates adenylate cyclase.
A human gene encoding an orphan G-protein-coupled receptor named ACCA (adenylate cyclase
constitutive activator) was isolated from a genomic library using as a probe a DNA fragment obtained
by low-stringency PCR. Human ACCA (hACCA) is a protein of 330 amino acids that exhibits all the
structural hallmarks of the main family of G-protein-coupled receptors and has a stretch of N-terminal sequence. Expression of hACCA resulted
in a dramatic stimulation of adenylate cyclase, similar in amplitude to that obtained with other
Gs-coupled receptors fully activated by their respective ligands. This stimulation was obtained in a
large variety of stable cell lines derived from various organs, and originating from different mammalian
species. hACCA was found to be the human homologue of a recently reported mouse orphan receptor
(GPCR21). The mouse ACCA (mACCA) was therefore recloned by PCR, and expression of
mACCA in Cos-7 cells demonstrated that the mouse receptor behaved similarly as a constitutive
activator of adenylate cyclase. It is not known presently whether the stimulation of adenylate cyclase is
the result of a true constitutive activity of the receptor or, alternatively, is the consequence of a
permanent stimulation by a ubiquitous ligand. The tissue distribution of mACCA was determined by
RNase protection assay. Abundant transcripts were found in the brain, whereas lower amounts were
detected in testis, ovary and eye. Various hypotheses concerning the constitutive activity of ACCA and
their potential biological significance are discussed.
THis receptor is also called GPR10 and found to be activated by a prolactin-releasing peptide Hinuma et al .
NCBI Summary: This gene is a member of the G protein-coupled receptor family and is found in the cell membrane. G protein-coupled receptors, characterized by a seven transmembrane domain motif, are involved in translating outside signals into G protein mediated intracellular effects. The encoded protein activates adenylate cyclase and modulates amyloid-beta production in a mouse model, suggesting that it may play a role in Alzheimer's disease. [provided by RefSeq, Oct 2012] |
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| General function | Receptor | ||||
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| Cellular localization | Plasma membrane | ||||
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| Ovarian function | Oocyte maturation | ||||
| Comment | The G Protein Coupled Receptor 3 Is Involved in cAMP and cGMP Signaling and Maintenance of Meiotic Arrest in Porcine Oocytes. Yang CR et al. The arrest of meiotic prophase in mammalian oocytes within fully grown follicles is dependent on cyclic adenosine monophosphate (cAMP) regulation. A large part of cAMP is produced by the Gs-linked G-protein-coupled receptor (GPR) pathway. In the present study, we examined whether GPR3 is involved in the maintenance of meiotic arrest in porcine oocytes. Expression and distribution of GPR3 were examined by western blot and immunofluorescence microscopy, respectively. The results showed that GPR3 was expressed at various stages during porcine oocyte maturation. At the germinal vesicle (GV) stage, GPR3 displayed a maximal expression level, and its expression remained stable from pro-metaphase I (MI) to metaphase II (MII). Immunofluorescence staining showed that GPR3 was mainly distributed at the nuclear envelope during the GV stage and localized to the plasma membrane at pro-MI, MI and MII stages. RNA interference (RNAi) was used to knock down the GPR3 expression within oocytes. Injection of small interfering double-stranded RNA (siRNA) targeting GPR3 stimulated meiotic resumption of oocytes. On the other hand, overexpression of GPR3 inhibited meiotic maturation of porcine oocytes, which was caused by increase of cGMP and cAMP levels and inhibition of cyclin B accumulation. Furthermore, incubation of porcine oocytes with the GPR3 ligand sphingosylphosphorylcholine (SPC) inhibited oocyte maturation. We propose that GPR3 is required for maintenance of meiotic arrest in porcine oocytes through pathways involved in the regulation of cAMP and cGMP. The Gs-linked receptor GPR3 maintains meiotic arrest in mammalian oocytesMehlmann LM, et al . Mammalian oocytes are held in prophase arrest by an unknown signal from the surrounding somatic cells. Here we show that the orphan Gs-linked receptor GPR3, which is localized in the oocyte, maintains this arrest. Oocytes from Gpr3 knockout mice resume meiosis within antral follicles, independently of an increase in luteinizing hormone, and this phenotype can be reversed by injection of Gpr3 RNA into the oocytes. Thus, the GPR3 receptor is a link in communication between the somatic cells and oocyte of the ovarian follicle and is crucial for the regulation of meiosis. The Xenopus laevis isoform of G protein-coupled receptor 3 (GPR3) is a constitutively active cell surface receptor that participates in maintaining meiotic arrest in X. laevis oocytes. Deng J et al. Oocytes are held in meiotic arrest in prophase I until ovulation, when gonadotropins trigger a subpopulation of oocytes to resume meiosis in a process termed 'maturation.' Meiotic arrest is maintained through a mechanism whereby constitutive cAMP production exceeds phosphodiesterase-mediated degradation, leading to elevated intracellular cAMP. Studies have implicated a constitutively activated Galpha(s)-coupled receptor, G protein-coupled receptor 3 (GPR3), as one of the molecules responsible for maintaining meiotic arrest in mouse oocytes. Here we characterized the signaling and functional properties of GPR3 using the more amenable model system of Xenopus laevis oocytes. We cloned the X. laevis isoform of GPR3 (XGPR3) from oocytes and showed that overexpressed XGPR3 elevated intraoocyte cAMP, in large part via Gbetagamma signaling. Overexpressed XGPR3 suppressed steroid-triggered kinase activation and maturation of isolated oocytes, as well as gonadotropin-induced maturation of follicle-enclosed oocytes. In contrast, depletion of XGPR3 using antisense oligodeoxynucleotides reduced intracellular cAMP levels and enhanced steroid- and gonadotropin-mediated oocyte maturation. Interestingly, collagenase treatment of Xenopus oocytes cleaved and inactivated cell surface XGPR3, which enhanced steroid-triggered oocyte maturation and activation of MAPK. In addition, human chorionic gonadotropin-treatment of follicle-enclosed oocytes triggered metalloproteinase-mediated cleavage of XGPR3 at the oocyte cell surface. Together, these results suggest that GPR3 moderates the oocyte response to maturation-promoting signals, and that gonadotropin-mediated activation of metalloproteinases may play a partial role in sensitizing oocytes for maturation by inactivating constitutive GPR3 signaling. | ||||
| Expression regulated by | FSH | ||||
| Comment | FSH Modulates PKAI and GPR3 Activities in Mouse Oocyte of COC in a Gap Junctional Communication (GJC)-Dependent Manner to Initiate Meiotic Resumption. Li J et al. Many studies have shown that cyclic adenosine-5'-monophosphate (cAMP)-dependent protein kinase A (PKA) and G-protein-coupled receptor 3 (GPR3) are crucial for controlling meiotic arrest in oocytes. However, it is unclear how gonadotropins modulate these factors to regulate oocyte maturation, especially by gap junctional communication (GJC). Using an in vitro meiosis-arrested mouse cumulus-oocyte complex (COC) culture model, we showed that there is a close relationship between follicle-stimulating hormone (FSH) and the PKA type I (PKAI) and GPR3. The effect of FSH on oocyte maturation was biphasic, initially inhibitory and then stimulatory. During FSH-induced maturation, rapid cAMP surges were observed in both cumulus cells and oocyte. Most GJC between cumulus cells and oocyte ceased immediately after FSH stimulation and recommenced after the cAMP surge. FSH-induced maturation was blocked by PKAI activator 8-AHA-cAMP. Levels of PKAI regulatory subunits and GPR3 decreased and increased, respectively, after FSH stimulation. In the presence of the GJC inhibitor carbenoxolone (CBX), FSH failed to induce the meiotic resumption and the changes in PKAI, GPR3 and cAMP surge in oocyte were no longer detected. Furthermore, GPR3 was upregulated by high cAMP levels, but not by PKAI activation. When applied after FSH stimulation, the specific phosphodiesterase 3A (PDE3A) inhibitor cilostamide immediately blocked meiotic induction, regardless of when it was administered. PKAI activation inhibited mitogen-activated protein kinase (MAPK) phosphorylation in the oocytes of COCs, which participated in the initiation of FSH-induced meiotic maturation in vitro. Just before FSH-induced meiotic maturation, cAMP, PKAI, and GPR3 returned to basal levels, and PDE3A activity and MAPK phosphorylation increased markedly. These experiments show that FSH induces a transient increase in cAMP levels and regulates GJC to control PKAI and GPR3 activities, thereby creating an inhibitory phase. After PDE3A and MAPK activities increase, meiosis resumes. Oocyte-specific expression of Gpr3 is required for the maintenance of meiotic arrest in mouse oocytesMehlmann LM.2005 . The maintenance of meiotic prophase arrest in mouse oocytes within fully grown follicles, prior to the surge of luteinizing hormone (LH) that triggers meiotic resumption, depends on a high level of cAMP within the oocyte. cAMP is produced within the oocyte, at least in large part, by the G(s)-linked G-protein-coupled receptor, GPR3. Gpr3 is localized in the mouse oocyte but is also present throughout the follicle. To investigate whether Gpr3 in the follicle cells contributes to the maintenance of meiotic arrest, RNA interference (RNAi) was used to reduce the amount of Gpr3 RNA within follicle-enclosed oocytes. Follicle-enclosed oocytes injected with small interfering double-stranded RNA (siRNA) targeting Gpr3, but not control siRNAs, stimulated the resumption of meiosis in the majority of oocytes following a 3-day culture period. Reduction of RNA was specific for Gpr3 because an unrelated gene was not reduced by microinjection of siRNA. Meiotic resumption was stimulated in isolated oocytes injected with the same siRNA and cultured for 1 to 2 days, but at a much lower rate than in follicle-enclosed oocytes that could be cultured for longer. These results demonstrate that GPR3 specifically in the oocyte, rather than in the follicle cells, is responsible for maintenance of meiotic arrest in mouse oocytes. Furthermore, the method developed here for specifically reducing RNA in follicle-enclosed oocytes, which can be cultured for a sufficient time to reduce the level of endogenous protein, should be generally useful for targeting a wide range of other proteins that may be involved in meiotic arrest, the resumption of meiosis, fertilization, or early embryonic development. | ||||
| Ovarian localization | Oocyte, Cumulus | ||||
| Comment | The porcine Gpr3 gene: molecular cloning, characterization and expression level in tissues and cumulus-oocyte complexes during in vitro maturation. Zhang B et al. G protein-coupled receptor 3 (Gpr3) is a member of G protein-coupled receptor rhodopsin family, which is present throughout the follicle within the ovary and functions as a critical factor for the maintenance of meiotic prophase arrest in oocytes by a Gs protein-mediated pathway. In the current paper, attempts were made to clone and characterize a gene encoding Gpr3 from pigs and investigate its expression pattern in tissues and the whole cumulus-oocyte complexes (COCs) in vitro maturation (IVM). Rapid amplification of cDNA ends and RT-PCR gave rise to the full sequence of Gpr3 gene with its length being 2101?bp nucleotides, including an open reading frame of 993?bp, encoding a 331 amino acid polypeptide with the molecular weight of 35.2?kDa. Homology search and sequence multi-alignment demonstrated that the putative porcine Gpr3 protein sequence shared a high identity with other animal Gpr3 orthologs, including several highly conservative motifs and amino acids. Real-time PCR analysis showed that the Gpr3 gene was expressed in tissues of cerebrum, cerebellum, hypothalamus, pituitary, ovary, oviduct, uterus, heart, liver, spleen, lung, kidney, muscle, fat, testis, thymus and granulosa cell, oocyte and COCs at different expression levels. The expression levels of this gene in oocyte, uterus, liver, fat, pituitary and brain were higher than that in other tissues. Interestingly, the mRNA and protein levels of Gpr3 in the whole COCs were down-regulated, and its mRNA expression levels were significantly and negatively correlated with the degrees of cumulus expansion (r?=?-0.937, P?Freudzon et al . The arrest of meiotic prophase in mouse oocytes within antral follicles requires the G protein G(s) and an orphan member of the G protein-coupled receptor family, GPR3. To determine whether GPR3 activates G(s), the localization of Galpha(s) in follicle-enclosed oocytes from Gpr3(+/+) and Gpr3(-/-) mice was compared by using immunofluorescence and Galpha(s)GFP. GPR3 decreased the ratio of Galpha(s) in the oocyte plasma membrane versus the cytoplasm and also decreased the amount of Galpha(s) in the oocyte. Both of these properties indicate that GPR3 activates G(s). The follicle cells around the oocyte are also necessary to keep the oocyte in prophase, suggesting that they might activate GPR3. However, GPR3-dependent G(s) activity was similar in follicle-enclosed and follicle-free oocytes. Thus, the maintenance of prophase arrest depends on the constitutive activity of GPR3 in the oocyte, and the follicle cell signal acts by a means other than increasing GPR3 activity. Immunolocalization and Expression Pattern of Gpr3 in the Ovary and Its Effect on Proliferation of Ovarian Granulosa Cells in Pigs. Zhang B et al. Gpr3, a member of the G protein-coupled receptor superfamily, was known as a critical factor for the maintenance of meiotic prophase arrest in oocytes via a Gs protein-mediated pathway. The present studies were conducted to examine the ovarian immunolocalization of Gpr3, its expression pattern in different stages of fetal, postnatal and developmental pigs and its effect on proliferation of ovarian granulosa cells in pigs. Immunohistochemical analysis indicated that Gpr3 was localized in egg nests, oocytes and granulosa cells (GCs) of the follicle ranging from the primordial to Graafian stages and the corpora lutea. Staining was faintly present in the corpora lutea and weak in GCs but was strong in oocytes. Real-time PCR and Western blotting indicated that Gpr3 mRNA and protein were both present in the different ages of ovaries, and there were wavy changes in the expression levels from postpartum 1 to 180 days. Moreover, both the mRNA and protein levels of Gpr3 were upregulated significantly during follicle growth, suggesting that Gpr3 might play potential roles in regulating ovarian follicle development in the pig. MTT and flow cytometry analyses indicated that Gpr3 knockdown significantly promoted proliferation of porcine GCs while increasing the proportion of cells in the S phase and the expression of Cyclin B1 and Cyclin D2, providing new insights into how Gpr3 signaling regulates the proliferation of porcine GCs. In conclusion, the stage- and cell-specific expression pattern of Gpr3 in the porcine ovary suggested that Gpr3 might play an important role during the entire process of follicular development and luteinization. zyx | ||||
| Follicle stages | Antral, Preovulatory | ||||
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| Phenotypes | |||||
| Mutations |
4 mutations
Species: mouse
Species: mouse
Species: mouse
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Jan. 17, 2002, 12:10 p.m. | by: |
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| last update: | March 19, 2014, 10:02 a.m. | by: | hsueh email: |
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