The importance of the cytosolic C-terminal region of the P2X7 receptor (P2X7R) is unquestioned, yet little is known about the functional domains of this region and how they may contribute to the numerous properties ascribed to this receptor. A structure-function analysis of truncated and single-residue-mutated P2X7 receptors was performed in HEK-293 cells and Xenopus oocytes. Cells expressing receptors truncated at residue 581 (of 595) have negligible ethidium ion uptake, whereas those

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... g the P2X7R truncated at position 582 give wild type ethidium ion uptake suggesting that pore formation requires over 95% of the C-terminal tail. Channel function was evident even in receptors that were truncated at position 380 indicating that only a small portion of the cytosolic region is required for channel activity. Surprisingly, truncations in the region between residues 551 and 581 resulted in non-functional receptors with no detectable cell surface expression in HEK-293 cells. A more detailed analysis revealed that mutations of single residues within this region could also abolish receptor function and cell surface expression, suggesting that this region may participate in regulating the surface expression of the pore-forming P2X7R. The P2X7R 1 is a ligand-gated ion channel and the seventh member of the P2X family (1). Exposure to ATP or the more potent agonist BzATP to the P2X7R renders the P2X7R permeant to Na ϩ , K ϩ , and Ca 2ϩ (2). Repeated or prolonged application of either agonist induces the formation of a cytolytic pore that is permeable to larger cations such as positively charged ethidium or N-methyl-D-glucamine (3, 4). The ability of the P2X7R to form pores is dependent on experimental conditions. Factors such as the duration of the agonist application, the presence of divalent cations, extracellular pH, receptor density, and receptor species influence pore formation (1, 4 -6).