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CELLULAR AND MOLECULAR

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

Department of Cell Physiology and Pharmacology, Maurice Shock Medical Sciences Building, University of Leicester, Leicester, United Kingdom (T.D.W., G.B.W.); and Molecular Pharmacology, Enabling Science and Technology, AstraZeneca, Cheshire, United Kingdom (G.F.W.)

We have shown previously that activation of endogenously expressed, G_q/11-coupled P2Y₂ nucleotide receptors with UTP reveals an intracellular Ca²⁺ response to activation of recombinant, G_i-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 G-scavenger G_t1 (transducin subunit), indicating the involvement of G_q and G subunits, respectively.

Address correspondence to: Dr. Gary B. Willars, Department of Cell Physiology and Pharmacology, University of Leicester, University Rd., Leicester LE1 9HN, UK. E-mail: gbw2{at}le.ac.uk

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