P2X7 and phospholipid signalling: the search of the "missing link" in epithelial cells

The purinergic receptor P2X(7) is widely expressed in epithelial cells. This receptor shares in common with the other P2X receptors the ability to form a non-selective cation channel. On the other hand, the COOH terminus of P2X(7) seems to allow this receptor to couple to a spectrum of downstream effectors responsible for the regulation of cell death and pore formation among other functions. However, the coupling of P2X(7) to these downstream effectors, as well as the identity of possible adapters directly interacting with the receptor, remains poorly understood. Here we review the ability of P2X(7) to activate phospholipid signalling pathways in epithelial cells and propose this step as a possible link between the receptor and other downstream effectors. The P2X(7) ability to control the cellular levels of several lipid messengers (PA, AA, DAG, ceramide, etc.) through the modulation of phospholipases (C, A(2), D) and neutral sphingomyelinase is described. These pathways are sometimes regulated independently of the channel function of the receptor. Recent data concerning P2X(7) localization in lipid rafts is also discussed in relation to the coupling to these pathways and dissociation from channel function.