P2X7 receptor as a double-edged sword: Neurotrophic and neurotoxic effects

Strong activation of the P2X7 receptor (P2X7R) by extracellular ATP is excitotoxic to neurons during brain ischemia or in spinal cord injury. In addition, activation of P2X7R in microglia is known to cause neuroinflammation and consequently neurodegeneration. This review focuses mainly on the direct effects of activation of P2X7R in neurons. P2X7R is an ATP-gated, nonselective ion channel that provides an influx pathway for Na+ and Ca2+, and upon sustained ATP stimulation, dilates into a pore permeable to molecules up to 900 Da. Mechanisms governing P2X7R-mediated cell death due to Ca2+ overload in the cytosol and possible involvement of perturbation of Ca2+ homeostasis in the endoplasmic reticulum and mitochondria are also discussed. In contrast to strong P2X7R activation, basal and mild activation of the P2X7R have been known to exert both antiapoptotic and proliferative effects in cancer cells, glial cells, and some neuroblastomas. How these effects are related to endoplasmic reticulum and mitochondrial Ca2+ homeostasis are described. In addition, the putative role that mild P2X7R activation plays as a neurotrophic signal is discussed.