PI3-kinase/Akt pathway-regulated membrane insertion of acid-sensing ion channel 1a underlies BDNF-induced pain hypersensitivity

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 AS...

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Bibliographic Details
Published in:The Journal of neuroscience 2012-05, Vol.32 (18), p.6351-6363
Main Authors: Duan, Bo, Liu, Di-Shi, Huang, Yu, Zeng, Wei-Zheng, Wang, Xiang, Yu, Hui, Zhu, Michael X, Chen, Zhe-Yu, Xu, Tian-Le
Format: Article
Language:English
Subjects:
Acid Sensing Ion Channels
Animals
Brain-Derived Neurotrophic Factor
Cell Membrane - metabolism
Hyperalgesia - chemically induced
Hyperalgesia - metabolism
Male
Mice
Mice, Knockout
Nerve Tissue Proteins - metabolism
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction - drug effects
Sodium Channels - metabolism
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Summary: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.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/jneurosci.4479-11.2012