标题：PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity
作者：Duan, Bo; Liu, Di-Shi; Huang, Yu; Zeng, Wei-Zheng; Wang, Xiang; Yu, Hui; Zhu, Michael X.; Chen, Zhe-Yu; Xu, Tian-Le
作者机构：[Liu, Di-Shi; Zeng, Wei-Zheng; Wang, Xiang; Xu, Tian-Le] Shanghai Jiao Tong Univ, Sch Med, Inst Med Sci, Dept Biochem & Mol Cell Biol,Neurosci Div, Sh 更多
通讯作者地址：[Xu, TL]Shanghai Jiao Tong Univ, Sch Med, Inst Med Sci, Dept Biochem & Mol Cell Biol,Neurosci Div, 280 S Chongqing Rd, Shanghai 200025, Peoples R Chin 更多
来源：JOURNAL OF NEUROSCIENCE
摘要：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.