Extracellular ATP elicits functional responses in many cell types by activating both G-protein coupled receptors (P2Y class) and ionotropic ATP-gated channel receptors (P2X class). The cDNAs or genes encoding seven different P2Y-class receptors and seven different P2X class receptors have been recently cloned. Despite this large and growing number of nucleotide receptor subtypes, few groups have investigated the factors which dictate expression of particular P2 receptors in different tissues and cell types. Our studies indicate that at least four ATP receptor subtypes are differentially expressed in mature phagocytic leukocytes and in myeloid progenitor cells. The expression of certain ATP receptors is down-regulated, while others are up- regulated, when phagocytic leukocytes are treated with various proinflammatory cytokines. We propose that differential expression of ATP receptor subtypes in various phagocyte subpopulations indicates that these leukocytes utilize locally released ATP and particular ATP receptors for distinct types of autocrine/ paracrine communication. This hypothesis addresses the exciting possibility that the regulated expression of P2 receptor subtypes is a critical aspect of the inflammatory process. Understanding the physiological and pathophysiological roles of extracellular ATP in various inflammatory cascades will require characterization of multiple aspects of P2 receptor expression, activation, and signal transduction biochemistry as proposed in these specific aims: 1) To characterize the programmed expression of ATP receptor subtypes during the differentiation of myeloid progenitor cells into granulocytes or monocyte/ macrophages. 2) To define the signaling cascades which mediate the activation or repression of ATP receptor subtype expression during inflammatory activation of myeloid cells. 3) To characterize the unique signaling pathways activated by the pore-forming P2X7/P2Z receptors expressed in tissue monocyte/ macrophages. These pathways converge on processes involved in cytolysis, cytokine processing, and apoptosis. 4) To characterize the potential role of ionotropic P2X1 receptors, which are expressed in the blood leukocytes, in modulating selectin-based rolling of these leukocytes on endothelial surfaces. 5) To characterize the role of the G-protein coupled P2Y2 receptors in regulating integrin- mediated adhesion of phagocytic leukocytes to vascular endothelial cells.
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