UDP-glucose acting at P2Y14 receptors is a mediator of mast cell degranulation

UDP-glucose (UDPG), a glycosyl donor in the biosynthesis of carbohydrates, is an endogenous agonist of the G protein-coupled P2Y14 receptor. RBL-2H3 mast cells endogenously express a P2Y14 receptor at which UDPG mediates degranulation as indicated by β-hexosaminidase (HEX) release. Both UDPG and a more potent, selective 2-thio-modified UDPG analog, MRS2690 (diphosphoric acid 1-α-d-glucopyranosyl ester 2-[(2-thio)uridin-5″-yl] ester), caused a substantial calcium transient in RBL-2H3 cells, which was blocked by pertussis toxin, indicating the presence of the Gi-coupled P2Y14 receptor, supported also by quantitative detection of abundant mRNA. Expression of the closely related P2Y6 receptor was over 100 times lower than the P2Y14 receptor, and the P2Y6 agonist 3-phenacyl-UDP was inactive in RBL-2H3 cells. P2Y14 receptor agonists also induced [35S]GTPγS binding to RBL-2H3 cell membranes, and phosphorylation of ERK1/2, P38 and JNK. UDPG and MRS2690 concentration-dependently enhanced HEX release with EC50 values of 1150 ± 320 and 103 ± 18 nM, respectively. The enhancement was completely blocked by pertussis toxin and significantly diminished by P2Y14 receptor-specific siRNA. Thus, mast cells express an endogenous P2Y14 receptor, which mediates Gi-dependent degranulation and is therefore a potential novel therapeutic target for allergic conditions.

Inhibition of the P2Y14 receptor may be a novel target for therapeutic intervention of asthma and allergic conditions.Figure optionsDownload as PowerPoint slide