QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, March 18, 2009, 29(11):3518-3528; doi:10.1523/JNEUROSCI.5714-08.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Trang, T. Articles by Salter, M. W. Search for Related Content PubMed PubMed Citation Articles by Trang, T. Articles by Salter, M. W.

 Previous Article  |  Next Article 

Neurobiology of Disease
P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

Tuan Trang,^1,2,3 Simon Beggs,^1,2,3 Xiang Wan,^1,2,3 and Michael W. Salter^1,2,3

¹Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8, ²Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and ³University of Toronto Centre for the Study of Pain, Toronto, Ontario, Canada M5G 1X8

Correspondence should be addressed to Dr. Michael W. Salter, Program in Neurosciences & Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: Email: mike.salter{at}utoronto.ca

Microglia in the dorsal horn of the spinal cord are increasingly recognized as being crucial in the pathogenesis of pain hypersensitivity after injury to a peripheral nerve. It is known that P2X4 purinoceptors (P2X4Rs) cause the release of brain-derived neurotrophic factor (BDNF) from microglia, which is necessary for maintaining pain hypersensitivity after nerve injury. However, there is a critical gap in understanding how activation of microglial P2X4Rs leads to the release of BDNF. Here, we show that stimulating P2X4Rs with ATP evokes a biphasic release of BDNF from microglia: an early phase occurs within 5 min, whereas a late phase peaks 60 min after ATP stimulation. Concomitant with the late phase of release is an increased level of BDNF within the microglia. Both phases of BDNF release and the accumulation within the microglia are dependent on extracellular Ca²⁺. The late phase of BDNF release and accumulation, but not the early phase of release, are suppressed by inhibiting transcription and translation, indicating that activation of P2X4R causes an initial release of a pre-existing pool of BDNF followed by an increase in de novo synthesis of BDNF. The release of BDNF is abolished by inhibiting SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-mediated exocytosis. Furthermore, we find that the P2X4R-evoked release and synthesis of BDNF are dependent on activation of p38-mitogen-activated protein kinase (MAPK). Together, our findings provide a unifying mechanism for pain hypersensitivity after peripheral nerve injury through P2X4R-evoked increase in Ca²⁺ and activation of p38-MAPK leading to the synthesis and exocytotic release of BDNF from microglia.

---

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

Correspondence should be addressed to Dr. Michael W. Salter, Program in Neurosciences & Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: Email: mike.salter{at}utoronto.ca

This article has been cited by other articles:

				A. K. Clark, P. K. Yip, and M. Malcangio The Liberation of Fractalkine in the Dorsal Horn Requires Microglial Cathepsin S J. Neurosci., May 27, 2009; 29(21): 6945 - 6954. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help