The role of P2Y and other P2Y receptors in degranulation of human LAD2 mast cells.

Mast cell degranulation affects many conditions, e.g., asthma and urticaria. We explored the potential role of the P2Y receptor (P2YR) and other P2Y subtypes in degranulation of human LAD2 mast cells. All eight P2YRs were expressed at variable levels in LAD2 cells (quantitative real-time RT-PCR). Gene expression levels of ADP receptors, P2YR, P2YR, and P2YR, were similar, and P2YR and P2YR were highly expressed at 5.8- and 3.8-fold of P2YR, respectively. Least expressed P2YR was 40-fold lower than P2YR, and P2YR and P2YR were ≤50 % of P2YR. None of the native P2YR agonists alone induced β-hexosaminidase (β-Hex) release, but some nucleotides significantly enhanced β-Hex release induced by C3a or antigen, with a rank efficacy order of ATP > UDPG ≥ ADP >> UDP, UTP. Although P2YR and P2YR are highly expressed, they did not seem to play a major role in degranulation as neither P2YR agonist UTP nor P2YR agonists ATPγS and NF546 had a substantial effect. P2YR-selective agonist MRS2365 enhanced degranulation, but ~1,000-fold weaker compared to its P2YR potency, and the effect of P2YR agonist 3-phenacyl-UDP was negligible. The enhancement by ADP and ATP appears mediated via multiple receptors. Both UDPG and a synthetic agonist of the P2YR, MRS2690, enhanced C3a-induced β-Hex release, which was inhibited by a P2YR antagonist, specific P2YR siRNA and pertussis toxin, suggesting a role of P2YR activation in promoting human mast cell degranulation. [ABSTRACT FROM AUTHOR]