PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity
PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity
复制标题
PI3 激酶/Akt 通路调节的酸敏感离子通道 1a 膜插入是 BDNF 诱导的疼痛超敏反应的基础
DOI：
10.1523/jneurosci.4479-11.2012
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发表时间：
2012-05-02
影响因子：
5.3
通讯作者：
Xu, Tian-Le
中科院分区：
文献类型：
--
作者：
Duan, Bo;Liu, Di-Shi;Xu, Tian-Le
中枢神经可塑性在痛觉过敏中起着关键作用。这一过程受脑源性神经营养因子(BDNF)的调节，也涉及1a型酸敏离子通道(ASIC1a)。然而，BDNF受体、原肌球蛋白相关激酶B(TrkB)和ASIC1a之间的相互作用尚不清楚。在这里，我们发现ASIC1基因的缺失抑制了鞘内应用BDNF所引起的小鼠持续性机械性痛敏。在培养的大鼠脊髓背角神经元和异种细胞中，BDNF/TrkB通路通过磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(PKB/Akt)级联和ASIC1a胞浆残基Ser-25的磷酸化增强ASIC1a电流，导致前向转运增强和表面表达增加。此外，在大鼠和小鼠中，这种增强的ASIC1a活性是BDNF介导的脊髓背角伤害性神经元超敏和中枢性机械痛觉过敏所必需的，这一过程可通过鞘内应用代表ASIC1a包含Ser-25的N末端区域的肽来取消。因此，我们的结果揭示了中枢敏化和疼痛超敏的新机制，并加强了ASIC1a通道在这些过程中的关键作用。
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.