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P2Y receptors: new subtypes, new functions

par Boeynaems, Jean-Marie ;Wilkin, Françoise ;Marteau, Frédéric ;Duhant, Xavier ;Savi, P.;Suarez Gonzalez, Nathalie ;Robaye, Bernard ;Communi, Didier
Référence Drug development research, 59, 1, page (30-35)
Publication Publié, 2003-05

Article révisé par les pairs

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Résumé :

The orphan receptor GPR86 was recently identified as a new ADP receptor coupled to Gi and named P2Y13. This brings to eight the number of genuine P2Y receptors. On the basis of sequence homology, they can be subdivided into two subgroups: P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11; and P2Y12, P2Y13, and the UDP-glucose receptor that should be renamed P2Y14. Some pharmacological properties of the P2Y13 receptor are significantly different from those of the P2Y12 receptor:• ATP and 2MeSATP behaved as weak partial agonists.• Potency of 2MeSADP was greater than or equal to that of ADP, depending on the expressing cell line and signaling pathway studied.• AR-C67085MX behaved as an antagonist, but only with a µM potency as compared to nM at the P2Y12 receptor.• The active metabolite of clopidogrel had no effect.Expression of P2Y13 mRNA was highest in brain, spleen, and various types of leukocytes, in particular dendritic cells. Recent results underscore the role of other P2Y receptors, especially P2Y11, in dendritic cell biology. Indeed, ATP and other nucleotides have multiple effects on human dendritic cells: potentiation of maturation, potentiation, or inhibition of IL-12p40 secretion (depending on the level of stimulation), inhibition of IL-12p70 production, potentiation of IL-10 secretion, and modulation of the repertoire of expressed chemokines and chemokine receptors. These actions are mediated by a rise in cAMP and the rank order of potency of various nucleotides is consistent with the involvement of the P2Y11 receptor. On the other hand, several nucleotides inhibit the proliferation of human CD4+ T-cells and their secretion of cytokines: these actions also involve a rise in cAMP, apparently mediated by a receptor other than P2Y11. These actions are reminiscent of those of PGE2 and might represent a protective mechanism operating during an exaggerated inflammatory response, when large amounts of nucleotides are released from damaged and dying cells. Drug Dev. Res. 59:30–35, 2003. © 2003 Wiley-Liss, Inc.