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The Journal of Neuroscience, March 25, 2009, 29(12):3781-3791; doi:10.1523/JNEUROSCI.5512-08.2009

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Neurobiology of Disease
The P2X₇ Receptor Drives Microglial Activation and Proliferation: A Trophic Role for P2X₇R Pore

Mastura Monif, Christopher A. Reid, Kim L. Powell, Megan L. Smart, and David A. Williams

Department of Physiology, The University of Melbourne, Melbourne, Victoria 3010, Australia

Correspondence should be addressed to Prof. David A. Williams, Department of Physiology, The University of Melbourne, Melbourne, Victoria 3010, Australia. Email: davidaw{at}unimelb.edu.au

Microglial activation is an integral part of neuroinflammation associated with many neurodegenerative conditions. Interestingly, a number of neurodegenerative conditions exhibit enhanced P2X₇ receptor (P2X₇R) expression in the neuroinflammatory foci where activated microglia are a coexisting feature. Whether P2X₇R overexpression is driving microglial activation or, conversely, P2X₇R overexpression is a consequence of microglial activation is not known. We report that overexpression alone of a purinergic P2X₇R, in the absence of pathological insults, is sufficient to drive the activation and proliferation of microglia in rat primary hippocampal cultures. The trophic responses observed in microglia were found to be P2X₇R specific as the P2X₇R antagonist, oxidized ATP (oxATP), was effective in markedly attenuating microgliosis. oxATP treatment of primary hippocampal cultures expressing exogenous P2X₇Rs resulted in a significant decrease in the number of activated microglia. P2X₇R is unusual in exhibiting two conductance states, a cation channel and a plasma membrane pore, and there are no pharmacological agents capable of cleanly discriminating between these two states. We used a point mutant of P2X₇R (P2X7RG345Y) with intact channel function but ablated pore-forming capacity to establish that the trophic effects of increased P2X₇R expression are exclusively mediated by the pore conductance. Collectively, and contrary to previous reports describing P2X₇R as a "death receptor," we provide evidence for a novel trophic role for P2X₇R pore in microglia.

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Received Nov. 16, 2008; revised Jan. 26, 2009; accepted Jan. 30, 2009.

Correspondence should be addressed to Prof. David A. Williams, Department of Physiology, The University of Melbourne, Melbourne, Victoria 3010, Australia. Email: davidaw{at}unimelb.edu.au

eLetters:

Read all eLetters

P2X7 as a trophic receptor

Francesco Di Virgilio, et al.

J. Neurosci. Online, 12 May 2009 [Full text]

A Trophic Role for P2X7R Pore

David A Williams, et al.

J. Neurosci. Online, 9 Jul 2009 [Full text]

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