A truncated naturally occurring variant of the human receptor P2X 7 was identified in cancer cervical cells. The novel protein (P2X 7-j ), a polypeptide of 258 amino acids, lacks the entire intracellular carboxyl terminus, the second transmembrane domain, and the distal third of the extracellular loop of the full-length P2X 7 receptor. The P2X 7-j was expressed in the plasma membrane; it showed diminished ligand-binding and channel function capacities and failed to form pores and mediate apoptosis in response to treatment with the P2X 7 receptor agonist benzoyl-ATP. The P2X 7-j interacted with the full-length P2X 7 in a manner suggesting heterooligomerization and blocked the P2X 7 -mediated actions. Interestingly, P2X 7-j immunoreactivity and mRNA expression were similar in lysates of human cancer and normal cervical tissues, but fulllength P2X 7 immunoreactivity and mRNA expression were higher in normal than in cancer tissues, and cancer tissues lacked 205-kDa P2X 7 immunoreactivity suggesting lack of P2X 7 homo(tri)-oligomerization. These results identify a novel P2X 7 variant with apoptosis-inhibitory actions, and demonstrate a distinct regulatory property for a truncated variant to antagonize its full-length counterpart through hetero-oligomerization. This may represent a general paradigm for regulation of a protein function by its variant.The receptor P2X 7 belongs to the P2X subfamily of P2 nucleotide receptors (1, 2), which are membrane-bound, ligand-operated channels (3-5). ATP is the naturally occurring ligand for the P2X 7 and activation of the receptor by brief exposure to extracellular ATP opens cation channels that allow Ca 2ϩ , Na ϩ , and K ϩ influx (6). Longer exposure to ATP allows passage of cations with progressively larger diameters, up to 900 Da, through formation of pores (7). The mechanism of pore formation is unclear, and opinions vary between decreased filter selectivity of existing channels (8) to rearrangement of receptor molecules (9). P2X 7 receptors function in a cell-specific manner and effects of receptor activation are determined by receptor expression (10), trafficking and plasma membrane localization (11-13), oligomerization (5), and postactivation internalization, recycling, and degradation (14). Expression of P2X 7 can be regulated hormonally; in human cervical epithelial cells epinephrine down-regulates expression of the glycosylated form of the P2X 7 and increases receptor degradation, and the effects can be potentiated by epidermal growth factor (15). Evidence for the physiological role of the P2X 7 comes from studies of P2X 7 -deficient mice, indicating its role in inflammatory (16) and immune processes (17). Epithelial cells of the female lower reproductive tract express the P2X 7 (18), and in human cervical epithelial cells ligand binding induces apoptosis by a mechanism that involves pore formation, augmented calcium influx, and calcium-dependent activation of the apoptotic mitochondrial pathway (19,20). Because human cervical epithelial cells secrete ATP into the extra...