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Electronic Letters to:
- Neurobiology of Disease:
Mastura Monif, Christopher A. Reid, Kim L. Powell, Megan L. Smart, and David A. Williams- The P2X7 Receptor Drives Microglial Activation and Proliferation: A Trophic Role for P2X7R Pore
J. Neurosci. 2009; 29: 3781-3791[Abstract] [Full text] [PDF]
eLetters: Submit a response to this article
Electronic letters published:
P2X7 as a trophic receptor
- Francesco Di Virgilio, Claudia Verderio, Maria Pia Abbracchio (12 May 2009)
- David A Williams, Mastura Monif, Christopher A. Reid (9 July 2009)
P2X7 as a trophic receptor 12 May 2009 
Francesco Di Virgilio,
Professor
University of Ferrara, Dept. Experimental and Diagnostic Medicine, 44100 Ferrara (Italy),
Claudia Verderio, Maria Pia AbbracchioSend letter to journal:
Re: P2X7 as a trophic receptor
fdv{at}unife.it Francesco Di Virgilio, et al.
In reference to the article by Monif et al. (2009) we wish to point out the following:
a) the finding that the P2X7 receptor, far from being a mere death-inducing receptor, mediates a trophic/growth promoting effect was originally published in 1999 by Di Virgilio and coworkers (Baricordi et al. 1999. Increased proliferation rate of lymphoid cells transfected with the P2X7 ATP receptor. J Biol Chem. 274:33206-8);
b) this initial observation was extended and strengthened again by Di Virgilio and co-workers in two human cancers (Adinolfi; et al. 2002. P2X7 receptor expression in evolutive and indolent forms of chronic lymphocytic leukemia. Blood 99: 706-708; Raffaghello et al. 2006. The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism. Cancer Res 66:907-914);
c) the crucial role of the P2X7 pore in sustaining P2X7-mediated growth was identified by Di Virgilio and co-workers in 2005 (Adinolfi et al. 2005. Basal activation of the P2X7 receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol Biol Cell 16: 3260-3272). Specifically, this paper showed that P2X7-receptor-mediated trophic activity requires a full pore-forming function and revealed a previously undescribed mechanism for growth stimulation by a plasma membrane pore;
d) the trophic/growth-promoting activity of the P2X7 receptor/pore in microglia was reported by Verderio, Abbracchio, Di Virgilio and collaborators in 2006 (Bianco et al. 2006. A role for P2X7 in microglial proliferation. J Neurochem 99:745-758).
None of the above studies was cited in the article by Monif et al.
Yours sincerely,
Francesco Di Virgilio Claudia Verderio Maria Pia Abbracchio
A Trophic Role for P2X7R Pore 9 July 2009 
David A Williams,
Professor
The University of Melbourne, Department of Physiology, Melbourne, Victoria, Australia, 3010,,
Mastura Monif, Christopher A. ReidSend letter to journal:
Re: A Trophic Role for P2X7R Pore
davidaw{at}unimelb.edu.au David A Williams, et al.
The work of many groups, including articles mentioned in correspondence, has created recent focus on the growth-promoting effects of the P2X7 receptor. Any omissions were not deliberate and this had been communicated on several occasions directly to the authors of this correspondence.
By using a full-length, single point mutant, P2X7R (G345Y), which lacks pore conductance but is normal in every other respect (cellular trafficking, ATP sensitivity, ion channel conductance), we were able to clearly and unambiguously identify, for the first time, that the P2X7R pore (rather than ion channel) was responsible for induction of microglial activation and proliferation.
Previous work (Adinolfi et al. 2005. Mol Biol Cell 16: 3260-3272) used a truncated receptor that lacked significant portions of the intracellular tail (which is known to be responsible for receptor folding, trafficking, and various cytoskeletal and signaling interactions), and that exhibited significantly limited ionic conductance. These limitations were shown previously by our group (Smart et al, 2003 JBC 278:8853-60), and were also acknowledged by Adinolfi and colleagues (2005), who described this truncation as creating a "lower conductance", "smaller channel". Allowing for inaccuracies in measuring absolute Ca2+ levels (i.e., fura-2 reporting range cannot extend beyond 2-5microM), the results of Fig 4E of Adinolfi et al. (2005) show that this receptor creates cells that are most similar to those subjected to mock transfection. Results from this inadequate control situation remain inconclusive.
We believe that the logical response of microglia to elevated ATP levels in endogenous settings (e.g., neurodegeneration) is P2X7R pore-mediated activation and proliferation, rather than their own "cell death".
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