RT Journal Article SR Electronic T1 Cross Talk between P2Y2 Nucleotide Receptors and CXC Chemokine Receptor 2 Resulting in Enhanced Ca2+ Signaling Involves Enhancement of Phospholipase C Activity and Is Enabled by Incremental Ca2+ Release in Human Embryonic Kidney Cells JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 661 OP 669 DO 10.1124/jpet.103.055632 VO 307 IS 2 A1 Tim D. Werry A1 Graeme F. Wilkinson A1 Gary B. Willars YR 2003 UL http://jpet.aspetjournals.org/content/307/2/661.abstract AB We have shown previously that activation of endogenously expressed, Gαq/11-coupled P2Y2 nucleotide receptors with UTP reveals an intracellular Ca2+ response to activation of recombinant, Gαi-coupled CXC chemokine receptor 2 (CXCR2) in human embryonic kidney cells. Here, we characterize further this cross talk and demonstrate that phospholipase C (PLC) and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]-dependent Ca2+ release underlies this potentiation. The putative Ins(1,4,5)P3 receptor antagonist 2-aminoethoxydiphenyl borane reduced the response to CXCR2 activation by interleukin-8, as did sustained inhibition of phosphatidylinositol 4-kinase with wortmannin, suggesting the involvement of phosphoinositides in the potentiation. Against a Li+ block of inositol monophosphatase activity, costimulation of P2Y2 nucleotide receptors and CXCR2 caused phosphoinositide accumulation that was significantly greater than that after activation of P2Y2 nucleotide receptors or CXCR2 alone, and was more than additive. Thus, PLC activity, as well as Ca2+ release, was enhanced. In these cells, agonist-mediated Ca2+ release was incremental in nature, suggesting that a potentiation of Ins(1,4,5)P3 generation in the presence of coactivation of P2Y2 nucleotide receptors and CXCR2 would be sufficient for additional Ca2+ release. Potentiated Ca2+ signaling by CXCR2 was markedly attenuated by expression of either regulator of G protein signaling 2 or the Gβγ-scavenger Gαt1 (transducin α subunit), indicating the involvement of Gαq and Gβγ subunits, respectively. The American Society for Pharmacology and Experimental Therapeutics