A Mechanism-Based Approach to P2X7 Receptor Action

The ligand-gated ion channel P2X7 receptor attracts special attention due to its widespread presence as well as its unusual responses. Besides relatively well-understood mechanisms such as intracellular Ca²⁺ increase and K⁺ depletion, the P2X7 receptor activates other peculiar responses whose mechanisms are not fully understood. The best known among these is the permeabilization of the cell membrane to large molecules. This permeabilization has been explained by the activation of a nonselective permeation pathway by the P2X7 receptor, a phenomenon called "pore formation." However, with the emergence of new data, it became apparent that large molecules enter the cell directly through the pore of the ion channel, similar to the smaller ions. This explanation seems to be true for cationic large molecules. On the other hand, there is still convincing evidence indicating that the P2X7 receptor activates a separate pathway that permeates anionic large molecules in some cell types. Furthermore, there exist functional data suggesting that the P2X7 receptor may also activate other intracellular signaling molecules or other ion channels. Interestingly and contrary to what is expected from a ligand-gated channel, these activations occur in a seemingly direct manner. Somewhat overshadowed by the pore formation hypothesis, these action mechanisms may lead to a better understanding of not only the P2X7 receptor itself but also some important physiologic functions such as the release of anionic autocoids/neurotransmitters in the central nervous system. This review discusses, assesses, and draws attention to the data concerning these neglected but potentially important points in the P2X7 receptor field.