Disease relevance of P2ry1

• This report implicates the P2Z/P2X7 receptor in the control of protein kinase cascades and transcriptional processes, and these observations are likely to be important for the development of selective purinergic receptor antagonists for the treatment of septic shock [1].
• P2Y1-deficient mice and mice treated with the P2Y1 antagonist MRS2179 displayed significantly less arterial thrombosis than their respective controls [2].
• Previous studies in experimental models revealed a role for the P2Y1 platelet ADP receptor in systemic vascular thromboembolism models [2].
• These results demonstrate a role for the P2Y1 receptor in both arterial and venous thrombosis, further establishing this receptor as a potential target for antithrombotic drugs [2].
• 5. C6 glioma cells express a P2Y-purinoceptor that inhibits adenylyl cyclase but does not activate phospholipase C. Expression of the human P2Y1-purinoceptor in C6 cells conferred 2MeSATP-stimulated inositol lipid hydrolysis to these cells [3].

High impact information on P2ry1

• We show here that the purinoceptor P2Y1 is required for platelet shape change in response to ADP and is also a principal receptor mediating ADP-induced platelet aggregation [4].
• Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice [4].
• In vivo, the lack of P2Y1 expression increased bleeding time and protected from collagen- and ADP-induced thromboembolism [4].
• The excitatory effects of medium samples and of ATP are blocked by purinergic receptor antagonists and by pretreatment with apyrase; these same purinergic receptor antagonists block propagation of electrically evoked calcium waves [5].
• Since ADP, AMP, and adenosine (in descending order) were less potent or ineffective in inducing the cation conductance, the involvement of a P2 purinergic receptor is proposed [6].

Chemical compound and disease context of P2ry1

• Inhibition of localized thrombosis in P2Y1-deficient mice and rodents treated with MRS2179, a P2Y1 receptor antagonist [2].
• The P2Y1 receptor is a Galpha q coupled G-protein receptor that is important for platelet shape change, aggregation, thromboxane A2 generation, procoagulant activity, adhesion to immobilized fibrinogen and thrombus formation under shear conditions [7].

Biological context of P2ry1

• These data show that altered autocrine-paracrine communication attributable to reduced levels of P2Y1 receptors in neural progenitor cells lacking Cx43 affects proliferation and migration but not cell differentiation during early CNS development [8].
• Cloning and tissue distribution of the human P2Y1 receptor [9].
• The corresponding amino acid sequence revealed 83% identity with the chick brain P2Y1 receptor and 34% with the murine neuroblastoma P2Y2 receptor [9].
• NF449 also antagonized the calcium rise mediated by the P2Y1 receptor, but with lower potency (IC50 = 5.8 +/- 2.2 microM; n = 3) [10].
• Total cell count in bronchoalveolar lavage fluids at 4 h and levels of IL-6 and macrophage inflammatory protein-2 in lung homogenates at 24 h postchallenge were significantly reduced in P2Y1/P2Y2-/- mice relative to wild-type mice [11].

Anatomical context of P2ry1

• Taken together, these results point to the presence of functional P2Y1 (ADP), P2Y2 (ATP, UTP) and P2Y6 (UDP) receptors on murine aorta endothelial cells [12].
• Purinergic receptor modulation of lipopolysaccharide signaling and inducible nitric-oxide synthase expression in RAW 264.7 macrophages [1].
• In COS-7 cells transfected with the coding sequence inserted into the pcDNA3 expression vector, 2-methylthioATP and ATP produced a strong stimulation of inositol phosphates, a typical response of a P2Y1 receptor [9].
• Megakaryocytes from P2Y1(-/-) mice lacked voltage-dependent Ca2+ release during the application of ADP but retained this response after stimulation of other Galphaq-coupled receptors [13].
• These were suramin and PPADS sensitive and essentially abolished in SCG glial cells cultured from adult P2Y1 receptor-deficient mice [14].

Associations of P2ry1 with chemical compounds

• P2Y4 receptors were not involved, since P2Y4-deficient mice displayed unaltered responses to ATP and UTP.The purinergic receptor antagonist suramin exerted surmountable antagonism for all agonists [12].
• The ATP/ATPgammaS-evoked relaxation and calcium signals in the knockout mice were partially rescued by P2Y1, as they were sensitive to 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS2179), a P2Y1-selective antagonist.In contrast to ATP, the UTP-evoked relaxation was not different between knockout and WT mice [15].
• Although depolarization enhanced Ca2+ mobilization resulting from GTPgammaS dialysis and to a lesser extent during AlF4- or thimerosal, these effects all required the presence of P2Y1 receptors [13].
• The P2Y1 receptor is responsible for ADP-induced shape change and weak and transient aggregation, while the P2Y12 receptor is responsible for the completion and amplification of the response to ADP and to all platelet agonists, including thromboxane A2 (TXA2), thrombin, and collagen [16].
• In platelets, the classical P2T receptor has now been resolved into three P2 receptor subtypes: the P2Y1, P2X1 and P2TAC receptors (the last of these, which is coupled to the inhibition of adenylate cyclase, is yet to be cloned) [17].

Physical interactions of P2ry1

• Effects of extracellular ATP and adenosine on different thymocyte subsets: possible role of ATP-gated channels and G protein-coupled purinergic receptor [18].

Other interactions of P2ry1

• Pharmacological screening with purinergic ligands indicated the presence of P2Y1 and P2Y2/4 receptors linked to the activation of a K+ current and P2X receptors, including P2X7, linked to the activation of a nonselective cationic current [19].
• We identified the expression of most of the purinergic receptor subtypes (A1, A2, P2X1, 3-7, P2Y1, 2, 4) mRNAs, analysed by the reverse transcriptase-polymerase chain reaction [20].
• A differential role of the platelet ADP receptors P2Y1 and P2Y12 in Rac activation [21].
• Combination of P2Y1 deficiency with P2Y12 inhibition led to a significant additive effect [2].
• 6 These results indicate the presence of several P2Y receptors coupled to an increase in intracellular calcium in the SCG: ADP-sensitive P2Y1 receptors and UDP-sensitive P2Y6 receptors in SCG neurons and glial cells, a novel UTP-sensitive P2Y receptor in SCG neurons and UTP- and ATP-sensitive P2Y2 receptors in SCG glia [14].

Analytical, diagnostic and therapeutic context of P2ry1

• Coexpression of TRPV1 mRNA with P2Y2 mRNA, but not P2Y1 mRNA, was determined in the rat lumbar DRG using in situ hybridization histochemistry [22].
• Based on the specific PCR product obtained and its Southern hybridization to the human P2Y1 receptor cRNA, the P2Y1 receptor gene was mapped to human chromosome 3q25 [23].

References