title: Activation of cytosolic phospholipase A2 in dorsal root ganglion neurons by Ca2+/calmodulin-dependent protein kinase II after peripheral nerve injury.
abstract: BACKGROUND
  Peripheral nerve injury leads to a persistent neuropathic pain state in which innocuous stimulation elicits pain behavior (tactile allodynia), but the underlying mechanisms have remained largely unknown. We have previously shown that spinal nerve injury induces the activation of cytosolic phospholipase A2 (cPLA2) in injured dorsal root ganglion (DRG) neurons that contribute to tactile allodynia. However, little is known about the signaling pathway that activates cPLA2 after nerve injury. In the present study, we sought to determine the mechanisms underlying cPLA2 activation in injured DRG neurons in an animal model of neuropathic pain, focusing on mitogen-activated protein kinases (MAPKs) and Ca2+/calmodulin-dependent protein kinase II (CaMKII).
  
  
  RESULTS
  Pharmacological inhibition of either p38 or extracellular signal-regulated kinase (ERK) in the injured DRG, which led to suppression of the development of tactile allodynia, did not affect cPLA2 phosphorylation and translocation after nerve injury. By contrast, a CaMKII inhibitor prevented the development and expression of nerve injury-induced tactile allodynia and reduced both the level of cPLA2 phosphorylation and the number of DRG neurons showing translocated cPLA2 in response to nerve injury. Applying ATP to cultured DRG neurons increased the level of both phosphorylated cPLA2 and CaMKII in the vicinity of the plasma membrane and caused physical association of these two proteins. In addition, ATP-stimulated cPLA2 and CaMKII phosphorylation were inhibited by both a selective P2X3R/P2X2+3R antagonist and a nonselective voltage-dependent Ca2+ channel (VDCC) blocker.
  
  
  CONCLUSIONS
  These results suggest that CaMKII, but not MAPKs, has an important role in cPLA2 activation following peripheral nerve injury, probably through P2X3R/P2X2+3R and VDCCs in primary afferent neurons.
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. shigeo_0121@yahoo.co.jp
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hasegawa
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kohro
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009475:Neurons, Afferent / Q000201:enzymology* / Q000378:metabolism; D010147:Pain Measurement; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018048:Receptors, Purinergic P2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048051:p38 Mitogen-Activated Protein Kinases; D054510:Phospholipases A2, Cytosolic