A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization

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 hetero-oligomerization 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 full-length 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.