LSC Abstract – Upregulation of P2X7R and Downstream Effects in Early Stages of Fibrogenesis

Several lung diseases are associated with extensive damage of pulmonary epithelia, and the regulatory mechanisms involved in their regeneration are not clearly defined. P2X receptors are cation selective ion channels activated by extracellular ATP. Recent work indicates that alveolar epithelial type I cells express P2X4 and P2X7 receptor subtypes in addition to a large number of other ion channels present in the alveolar epithelium. Up- or downregulation of their expression is associated with several disease states. For example, P2X7R activation inhibited the Wnt/beta-catenin signaling leading to alveolar epithelial type I (ATI) cell death. An important step is the activation ofglycogen synthase kinase 3beta (GSK-3beta) by phosphorylation of Tyr- 216 via P2X7R. Our previous studies have shown that the N-glycosylated P2X7R is localized in the plasma membrane and is partly associated with caveolae, containing the structure protein caveolin-1. We have shown that the P2X7R interacts with caveolin-1 in ATI cells. An injury induced ATP release, initiates via P2X7R a protein kinase C (PKC)-beta1 translocation from the cytoplasm to the lipid rafts. The expression of PKC-beta1 was repressed by the P2X7R inhibitor oxATP, suggesting that PKC-beta1 is downstream of P2X7R activation. In the present study using different injury models we investigated a possible involvement of thePKC-beta1 in the Wnt/β-catenin pathway and characterized subsequent ATI cell survival.