Disease relevance of P2RY13

• We demonstrate that in squamous cell carcinoma cells, stimulation with the GPCR agonists LPA or carbachol specifically results in metalloprotease cleavage and release of amphiregulin (AR) [1].
• In addition to their physiological roles in the cardiovascular system (CVS), G-protein-coupled receptor (GPCR) agonists such as noradrenaline, endothelin-1 and angiotensin II (Ang II) are known to be involved in the development of cardiac hypertrophy [2].
• Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, our results imply that alterations in GPCR signaling may account for some of its clinical manifestations [3].
• This induction of permissive SOCE in response to soluble E-selectin and PAF was shown to act through a G protein-coupled receptor (GPCR) coupled to pertussis toxin-insensitive G(q/11) [4].
• Here we show that this G protein-coupled receptor (GPCR) is also aberrantly expressed in a high percentage of human acute myeloid leukemias [5].

Psychiatry related information on P2RY13

• Many drugs of abuse signal through receptors that couple to G proteins (GPCRs), so the factors that control GPCR signaling are likely to be important to the understanding of drug abuse [6].
• Given the complexity of neurological disorders such as ischemic stroke, Alzheimer's disease and epilepsy, exploitation mGlu receptor-associated GPCR interactions may prove efficacious in the treatment of such disorders [7].

High impact information on P2RY13

• Future high-resolution structural studies of rhodopsin and other GPCRs will form a basis to elucidate the detailed molecular mechanism of GPCR-mediated signal transduction [8].
• Significantly, GPCR-containing CCPs are also functionally distinct, as their surface residence time is regulated locally by GPCR cargo via PDZ-dependent linkage to the actin cytoskeleton [9].
• Our results reveal a novel function of betaarr1 as a cytoplasm-nucleus messenger in GPCR signaling and elucidate an epigenetic mechanism for direct GPCR signaling from cell membrane to the nucleus through signal-dependent histone modification [10].
• (2005) provide evidence that beta-arrestin 1 moves to the nucleus in response to GPCR stimulation, where it regulates gene expression by facilitating histone acetylation at specific gene promoters [11].
• A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription [10].

Chemical compound and disease context of P2RY13

• In a variety of squamous cell carcinoma cell lines of the head and neck (HNSCCs), we found that treatment with the GPCR agonists lysophosphatidic acid (LPA), bradykinin, thrombin, and carbachol results in rapid tyrosine phosphorylation of the EGFR [12].
• In PC12 rat pheochromocytoma cells, both agents block lysophosphatidic acid (LPA)- and bradykinin-stimulated Erk 1/2 phosphorylation, suggesting that intact focal adhesion complexes are required for GPCR-induced mitogen-activated protein kinase activation in these cells [13].
• Here we report that a synthetic peptide derived from the NH2-terminal extracellular region of an orphan GPCR, GPR1 (GPR1ntP-(1-27); MEDLEETLFEEFENYSYDLDYYSLESC), inhibited infection of not only an HIV-1 variant that uses GPR1 as a co-receptor, but also X4, R5, and R5X4 viruses [14].
• Melatonin has been shown to bind to the MT1 G protein-coupled receptor (GPCR) in MCF-7 breast cancer cells to modulate the estrogen response pathway suppressing estrogen-induced estrogen receptor alpha (ERalpha) transcriptional activity, blunting ER/DNA binding activity and suppressing cell proliferation [15].
• This review focuses on the recent report of a mouse melanoma model, TG-3, which has implicated the ectopic expression of the metabotropic glutamate receptor 1 (Grm1), a G protein coupled receptor (GPCR), in melanomagenesis and metastasis [16].

Biological context of P2RY13

• We show that inhibition of proHB-EGF processing blocks GPCR-induced EGFR transactivation and downstream signals [17].
• GPCR desensitization occurs as a consequence of G protein uncoupling in response to phosphorylation by both second messenger-dependent protein kinases and G protein-coupled receptor kinases (GRKs) [18].
• The focus of this review is the current and evolving understanding of the contribution of GRKs, beta-arrestins, and endocytosis to GPCR-specific patterns of desensitization and resensitization [18].
• ALX at the level of DNA has sequence homology to the N-formylpeptide receptor and as an orphan GPCR was initially referred to as the N-formylpeptide receptor-like 1 [19].
• Allosteric sites on GPCRs represent novel drug targets because allosteric modulators possess a number of theoretical advantages over classic orthosteric ligands, such as a ceiling level to the allosteric effect and a potential for greater GPCR subtype-selectivity [20].

Anatomical context of P2RY13

• GPR94 was expressed in the frontal cortex, caudate putamen and thalamus of brain while GPR95 was expressed in the human prostate and rat stomach and fetal tissues [21].
• Our data suggest that OA1 represents the first example of an exclusively intracellular GPCR and support the hypothesis that GPCR-mediated signal transduction systems also operate at the internal membranes in mammalian cells [22].
• A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs [23].
• Another ArfGAP, Git2, was found to be a component of the Gbetagamma-mediated directional sensing machinery, while simultaneously playing an essential role in the suppressive control of superoxide production, which is mediated by vesicle transport in GPCR-stimulated neutrophils [24].
• Over the past three years, three types of scaffolds for GPCR-directed complex assembly have been identified: transactivated receptor tyrosine kinases (RTKs), integrin-based focal adhesions, and GPCRs themselves [25].

Associations of P2RY13 with chemical compounds

• Two other novel GPCR genes, GPR94 and GPR95, encoded a subfamily with the genes encoding the UDP-glucose and P2Y(12) receptors (sharing >50% identities in the TM regions) [21].
• We provide here structural evidence that the protein product of the ocular albinism type 1 gene (OA1), a pigment cell-specific integral membrane glycoprotein, represents a novel member of the GPCR superfamily and demonstrate that it binds heterotrimeric G proteins [22].
• MAP kinase activation may result from stimulation of either tyrosine-kinase (RTK) receptors, which possess intrinsic tyrosine kinase activity, or G-protein-coupled receptors (GPCR) [26].
• Conversely, stimulating ligand-gated channels, particularly those that are permeable to Ca(2+), indirectly produces effects on GPCRs and/or on GPCR-activated signaling cascades [27].
• Transient expression of either Gq- or Gi-coupled receptors in COS-7 cells allowed GPCR agonist-induced EGFR transactivation, and lysophosphatidic acid (LPA)-generated signals involved the docking protein Gab1 [28].

Other interactions of P2RY13

• The effect on ERK1 was inhibited by AR-C69931MX, a P2Y12 and P2Y13 antagonist [29].
• MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4nM at the P2Y1 receptor, with >10000-fold selectivity in comparison to P2Y12 and P2Y13 receptors [30].
• In contrast, activation of the P2Y12-, P2Y13-, and P2Y14-receptors causes an inhibition of adenylate cyclase activity [31].
• Regulated transcripts were validated using real-time quantitative RT-PCR, and immunohistochemistry was performed for the most significantly downregulated transcripts in MSA and PD putamen, GPR86 and RGS14, associated with G protein signaling and transcriptional regulation [32].
• CONCLUSIONS: The most interesting findings were the high mRNA expression of P2Y12 receptors in lymphocytes potentially explaining the anti-inflammatory effects of clopidogrel, P2Y13 receptors in monocytes and a previously unrecognised expression of P2X4 in lymphocytes and monocytes [33].

Analytical, diagnostic and therapeutic context of P2RY13

• Graded reductions in GPCR expression can be achieved through antisense strategies or total gene ablation or replacement can be achieved through gene targeting strategies, and exogenous expression of wild-type or mutant GPCR isoforms can be accomplished with transgenic technologies [34].
• Here, we report the molecular cloning of a novel GPCR for LTB(4), designated BLT2, which binds LTB(4) with a Kd value of 23 nM compared with 1.1 nM for BLT1, but still efficiently transduces intracellular signaling [35].
• Techniques: GPCR assembly, pharmacology and screening by flow cytometry [36].
• Many attempts have been made to design universal ligand-screening systems such that any GPCR can be screened using a common assay end-point [37].
• Using a degenerate PCR approach, we have identified 15 G protein-coupled receptors (GPCR) from human and rodent tissues [38].

References