PMID- 19295157
OWN - NLM
STAT- MEDLINE
DCOM- 20090413
LR  - 20220309
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 29
IP  - 11
DP  - 2009 Mar 18
TI  - P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor 
      in microglia is dependent on calcium and p38-mitogen-activated protein kinase 
      activation.
PG  - 3518-28
LID - 10.1523/JNEUROSCI.5714-08.2009 [doi]
AB  - 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 
      Ca(2+). 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 Ca(2+) and activation of p38-MAPK leading to the 
      synthesis and exocytotic release of BDNF from microglia.
FAU - Trang, Tuan
AU  - Trang T
AD  - Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, 
      Ontario, Canada M5G 1X8.
FAU - Beggs, Simon
AU  - Beggs S
FAU - Wan, Xiang
AU  - Wan X
FAU - Salter, Michael W
AU  - Salter MW
LA  - eng
GR  - Howard Hughes Medical Institute/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Receptors, Purinergic P2)
RN  - 0 (Receptors, Purinergic P2X4)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Animals, Newborn
MH  - Brain-Derived Neurotrophic Factor/*biosynthesis/metabolism
MH  - Calcium/*metabolism
MH  - Cells, Cultured
MH  - Enzyme Activation/physiology
MH  - Exocytosis/physiology
MH  - Microglia/enzymology/*metabolism
MH  - Molecular Sequence Data
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Purinergic P2/*physiology
MH  - Receptors, Purinergic P2X4
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism/physiology
PMC - PMC3589565
MID - CAMS2734
OID - NLM: CAMS2734
EDAT- 2009/03/20 09:00
MHDA- 2009/04/14 09:00
PMCR- 2009/09/18
CRDT- 2009/03/20 09:00
PHST- 2009/03/20 09:00 [entrez]
PHST- 2009/03/20 09:00 [pubmed]
PHST- 2009/04/14 09:00 [medline]
PHST- 2009/09/18 00:00 [pmc-release]
AID - 29/11/3518 [pii]
AID - 3465585 [pii]
AID - 10.1523/JNEUROSCI.5714-08.2009 [doi]
PST - ppublish
SO  - J Neurosci. 2009 Mar 18;29(11):3518-28. doi: 10.1523/JNEUROSCI.5714-08.2009.