Disease relevance of P2ry12

• Our data suggest that secretion of endogenous ADP and subsequent P2Y12-mediated signaling are critical for platelet aggregation, platelet spreading, and as a consequence, for stabilization of thrombus [1].
• Previously it was shown that stimulation of the P2Y12 receptor activates PKB signalling in C6 glioma cells [K. Van Kolen and H. Slegers, J. Neurochem. 89, 442.]. In the present study, the mechanisms involved in this response were further elucidated [2].

High impact information on P2ry12

• The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts [3].
• In addition, we showed the predominant association of P2Y12 oligomers to cell membrane lipid rafts and the partitioning of P2Y12 out of rafts in response to clopidogrel and Act-Met [3].
• Finally, using a series of receptors individually mutated at each cysteine residue and a chimeric P2Y12/P2Y13 receptor, we pointed out the involvement of cysteine 97 within the first extracellular loop of P2Y12 in the mechanism of action of Act-Met [3].
• P2Y12, a G protein-coupled receptor that plays a central role in platelet activation has been recently identified as the receptor targeted by the antithrombotic drug, clopidogrel [3].
• The raft-associated P2Y12 oligomers represented the functional form of the receptor, as demonstrated by binding and signal transduction studies [3].

Biological context of P2ry12

• Molecular genetic analysis revealed that OSP-1 was a homozygous for a mutation in the translation initiation codon (ATG to AGG) in the P2Y12 gene [1].
• In the present study, we report that the ADP-induced chemotaxis of microglia is mediated by P2Y12/13 receptors and is beta1 integrin-dependent in the presence of fibronectin [4].
• The phosphorylation was reduced both by removal of the extracellular Ca2+ and partially or almost completely by MRS2179 or AR-C69931MX, specific antagonists of the P2Y1 and P2Y12 receptors, respectively [5].

Anatomical context of P2ry12

• Selective expression of Gi/o-coupled ATP receptor P2Y12 in microglia in rat brain [6].
• Hardly any P2Y12 mRNA was detected in macrophages obtained from the spleen and abdominal cavity, which share many surface molecules with microglia [6].
• Expression of P2Y12 was also observed in naive and axotomized facial nuclei, and the number of P2Y12-expressing cells increased following facial nerve axotomy [6].
• The cellular localization of P2Y12 was investigated by in situ hybridization, and P2Y12 mRNA was detected in small cells distributed throughout the brain, including the hippocampus [6].
• These results show that P2Y12 receptors mediate an autoinhibition of transmitter release from PC12 cells and sympathetic neurons through an inhibition of voltage-gated Ca2+ channels [7].

Associations of P2ry12 with chemical compounds

• P2Y12 receptor stimulation inhibits beta-adrenergic receptor-induced differentiation by reversing the cyclic AMP-dependent inhibition of protein kinase B [8].
• To investigate how P2Y receptors are activated in a neuronal environment, we used PC12 cells in which nucleotides were found to elicit increases in inositol phosphates via P2Y2 and decreases in cAMP via P2Y12 receptors [9].
• These results indicate that nucleoside diphosphate-sensitive (P2Y12 and P2Y1) receptors are activated by spontaneous nucleotide release, whereas triphosphate-sensitive (P2Y2) receptors require an excess of depolarization-evoked release to become activated [9].

Other interactions of P2ry12

• 5. In conclusion, the data suggest that P2Y (P2Y1 or P2Y12) receptor subtypes are involved in the generation of astrogliosis in the NAc of rats, with a possible minor contribution of P2X receptor subtypes [10].

Analytical, diagnostic and therapeutic context of P2ry12

• In vitro treatment with Act-Met or in vivo oral administration to rats with clopidogrel induced the breakdown of these oligomers into dimeric and monomeric entities in P2Y12 expressing HEK293 and platelets respectively [3].
• Northern blot analysis demonstrated that P2Y12 is expressed predominantly in the brain, and to a lesser extent in the spleen [6].
• Selective expression of P2Y12 mRNA in microglia was confirmed by double-label in situ hybridization and immunohistochemistry with antibodies against NeuN and Iba1 as an immunohistochemical marker for neurons and microglia, respectively [6].
• We conclude that the rat brain Gi-linked ADP receptors, as revealed using [35S]GTPgammaS autoradiography, correspond to P2Y12 [11].

References