Rat P2X7 Receptor Show Functional Independence Between Macropore Formation and Scavenger Activity

The purinergic ionotropic receptor P2X7 stands out from other members of the P2X family due to its ability to form a macropore, activate multiple intracellular signaling pathways, and, as more recently reported, to mediate scavenger activity toward apoptotic cells. In addition, P2X7 exhibits a high number of single nucleotide polymorphisms (SNPs) and splice variants, several of which have been shown to impair ATP-mediated macropore formation. The aim of this study was to determine whether specific SNPs or deletion variants that have lost channel conductance or macropore activity retain other reported P2X7 functions. To address this, we analyzed the following variants: P2X7A (wild-type), P2X7B (unable to activate the macropore), P2X7 T283M (lacking conductance and macropore formation), P2X7 with N-terminal deletion (∆N; deficient in signal transduction), and P2X7 DN (dominant-negative double mutant W167A/C168A, lacking all known activities). We evaluated calcium influx, macropore formation, ERK and p38 signaling, and scavenger activity. Our results indicate that macropore formation depends on channel conductance, in contrast to what has been previously reported for P2X7B. Moreover, all modifications tested impaired signaling pathway activation. Strikingly, none of the mutations affected receptor-mediated phagocytic activity. These findings suggest that loss of conductance or macropore formation does not necessarily entail loss of other P2X7 functions, and our data reveals a functional independence between scavenger activity and the canonical roles of P2X7 (channel/macropore, MAPKs). This modular view provides a framework to reconcile the apparently discordant phenotypes of P2X7 variants observed across diverse pathophysiological settings.