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The P2X₇ purinergic receptor: from physiology to neurological disorders

Department of Pharmacology and Anesthesiology, University of Padova, Padova, Italy

¹ Correspondence: Department of Pharmacology and Anesthesiology, University of Padova, Largo "E. Meneghetti" 2, 35131 Padova, Italy. E-mail: stephen.skaper{at}unipd.it

Purine nucleotides are well established as extracellular signaling molecules. P2X receptors are ATP-gated cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord. Several P2X receptor subtypes, including P2X₇, have the unusual property of changing their ion selectivity during prolonged exposure to ATP, which results in progressive dilation of the channel pore and the development of permeability to molecules as large as 900 Da. The P2X₇ receptor was originally described in cells of hematopoietic origin, including macrophages, microglia, and certain lymphocytes, and mediates the influx of Ca²⁺ and Na⁺ ions, as well as the release of proinflammatory cytokines. P2X₇ receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1β, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X₇ receptors provides an inflammatory stimulus, and P2X₇ receptor-deficient mice have substantially attenuated inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2X₇ receptor activity, by regulating the release of proinflammatory cytokines, may be involved in the pathophysiology of depression. The P2X₇ receptor may thus represent a critical communication link between the nervous and immune systems, while providing a target for therapeutic exploitation. This review discusses the current biology and cellular signaling pathways of P2X₇ receptor function, as well as insights into the role for this receptor in neurological/psychiatric diseases, outstanding questions, and the therapeutic potential of P2X₇ receptor antagonism.—Skaper, S. D., Debetto, P., Giusti, P. The P2X₇ purinergic receptor: from physiology to neurological disorders.

Key Words: ATP • neurodegeneration • microglia • inflammation • cytokines • chronic pain • depression