title: PI3-kinase/Akt pathway-regulated membrane insertion of acid-sensing ion channel 1a underlies BDNF-induced pain hypersensitivity.
abstract: Central neural plasticity plays a key role in pain hypersensitivity. This process is modulated by brain-derived neurotrophic factor (BDNF) and also involves the type 1a acid-sensing ion channel (ASIC1a). However, the interactions between the BDNF receptor, tropomyosin-related kinase B (TrkB), and ASIC1a are unclear. Here, we show that deletion of ASIC1 gene suppressed the sustained mechanical hyperalgesia induced by intrathecal BDNF application in mice. In both rat spinal dorsal horn neurons and heterologous cell cultures, the BDNF/TrkB pathway enhanced ASIC1a currents via phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) cascade and phosphorylation of cytoplasmic residue Ser-25 of ASIC1a, resulting in enhanced forward trafficking and increased surface expression. Moreover, in both rats and mice, this enhanced ASIC1a activity was required for BDNF-mediated hypersensitivity of spinal dorsal horn nociceptive neurons and central mechanical hyperalgesia, a process that was abolished by intrathecal application of a peptide representing the N-terminal region of ASIC1a encompassing Ser-25. Thus, our results reveal a novel mechanism underlying central sensitization and pain hypersensitivity, and reinforce the critical role of ASIC1a channels in these processes.
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Duan
authors.forename: Di-Shi
authors.initials: DS
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Wei-Zheng
authors.initials: WZ
authors.lastname: Zeng
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.forename: Zhe-Yu
authors.initials: ZY
authors.lastname: Chen
authors.forename: Tian-Le
authors.initials: TL
authors.lastname: Xu
mesh_terms: D062565:Acid Sensing Ion Channels; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor; D002462:Cell Membrane / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D062565:Acid Sensing Ion Channels; D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D015222:Sodium Channels; C568267:ASIC1 protein, mouse; C568268:Asic1 protein, rat