The P2X7 receptor (P2X7R) is a ligand-gated non-selective cation channel activated by extracellular ATP. With prolonged ATP exposure the receptor pore dilates to accommodate larger cations up to 900Da and this promotes cell death. P2X7 receptors are not always found at the plasma membrane; cell- and species-dependent differences in its trafficking have been reported (1). These differences range from the receptor being predominantly intracellular to predominantly at the cell surface. Determinants of P2X7R trafficking have been identified within its uniquely long cytoplasmic tail, but mechanisms that regulate its trafficking remain poorly understood (2). P2X7 receptors are predominantly expressed in immune and epithelial cells in physiological conditions but are up-regulated in many other cell types in pathophysiological conditions. An example is fibroblasts, where up-regulation of P2X7R contributes to lung, kidney and pancreatic fibrosis (3,4,5). We are interested in the regulation of P2X7R in fibroblasts and the role of caveolin-1 in this regulation. Heterologous expression of P2X7R in fibroblast cell lines was surprisingly toxic compared to other epithelial cell lines. There was a correlation between toxicity and levels of caveolin-1 expression and over-expression of caveolin-1 in HEK293 or HeLa cells increased cell death associated with P2X7R expression. Increased expression of caveolin-1 increased targeting of P2X7R to lipid rafts, as measured by fractionation on a sucrose density gradient. To study the role of the P2X7R C-terminus in trafficking and targeting, we generated chimeras in which the C-terminal tail (Ct) of either rat or human P2X7 was fused downstream of the transmembrane region of CD8 alpha. Human P2X7R shows much greater ER retention than rat P2X7R. Expressed in HeLa cells, immunocytochemistry combined with flow cytometry showed that CD8a is expressed at the plasma membrane (pm) whereas the rat Ct chimera shows pm expression but more endoplasmic reticulum (ER) retention and the human Ct chimera, much greater ER retention. In the REF52 fibroblast cell line a different distribution was observed. The Ct chimeras were much more efficiently trafficked to the pm than in HeLas. This increased trafficking could explain the greater toxicity of P2X7R in these cells. Unlike CD8 a, which is excluded from lipid rafts, the P2X7 Ct chimeras showed targeting to the light raft fractions. There were two molecular mass species of the Ct chimeras consistent with a post-translational modification. Only the higher mass species was targeted to the raft fractions; this targeting was disrupted by coexpression of a dominant negative mutant of caveolin-1.