Cdk5-Dependent Phosphorylation of Cav3.2 T-Type Channels: Possible Role in Nerve Ligation-Induced Neuropathic Allodynia and the Compound Action Potential in Primary Afferent C Fibers
Cdk5-Dependent Phosphorylation of Cav3.2 T-Type Channels: Possible Role in Nerve Ligation-Induced Neuropathic Allodynia and the Compound Action Potential in Primary Afferent C Fibers
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DOI：
10.1523/jneurosci.0181-19.2019
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发表时间：
2020-01-08
影响因子：
5.3
通讯作者：
Felix, Ricardo
中科院分区：
文献类型：
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作者：
Gomez, Kimberly;Calderon-Rivera, Aida;Felix, Ricardo
电压门控 T 型 Ca2+ (Ca(v)3) 通道调节多种生理事件，包括神经元兴奋性，并与失神癫痫、心血管疾病和神经性疼痛等多种病理状况有关。人们还认识到，钙/钙调蛋白依赖性蛋白激酶 II 以及蛋白激酶 A 和 C 调节 T 型通道的活性。有趣的是，周围神经损伤会引起触觉异常性疼痛，并上调背根神经节 (DRG) 和脊髓背角中的 Ca(v)3.2 通道和细胞周期蛋白依赖性激酶 5 (Cdk5)。在此，我们报道 HEK293 细胞中表达的重组 Ca(v)3.2 通道是 Cdk5 的调节靶点。定点诱变表明，该调节的相关位点是残基 5561 和 S1987。我们还发现，Cdk5 可能调节脊髓神经结扎（SNL）诱导的机械性异常性疼痛大鼠中 Ca(v)3.2 通道的功能表达。因此，Cdk5 抑制剂奥洛穆辛影响脊神经中记录的复合动作电位以及缩爪阈值。同样，SNL 后 DRG 中的 Cdk5 表达也上调。这些发现揭示了磷酸化如何调节 Ca(V)3.2 通道的新机制，并表明 SNL 后 Cdk5 介导的磷酸化增加的通道活性有助于神经损伤引起的触觉异常性疼痛。
Voltage-gated T-type Ca2+ (Ca(v)3) channels regulate diverse physiological events, including neuronal excitability, and have been linked to several pathological conditions such as absence epilepsy, cardiovascular diseases, and neuropathic pain. It is also acknowledged that calcium/calmodulin-dependent protein kinase II and protein kinases A and C regulate the activity of T-type channels. Interestingly, peripheral nerve injury induces tactile allodynia and upregulates Ca(v)3.2 channels and cyclin-dependent kinase 5 (Cdk5) in dorsal root ganglia (DRG) and spinal dorsal horn. Here, we report that recombinant Ca(v)3.2 channels expressed in HEK293 cells are regulatory targets of Cdk5. Site-directed mutagenesis showed that the relevant sites for this regulation are residues 5561 and S1987. We also found that Cdk5 may regulate Ca(v)3.2 channel functional expression in rats with mechanical allodynia induced by spinal nerve ligation (SNL). Consequently, the Cdk5 inhibitor olomoucine affected the compound action potential recorded in the spinal nerves, as well as the paw withdrawal threshold. Likewise, Cdk5 expression was upregulated after SNL in the DRG. These findings unveil a novel mechanism for how phosphorylation may regulate Ca(V)3.2 channels and suggest that increased channel activity by Cdk5-mediated phosphorylation after SNL contributes nerve injury-induced tactile allodynia.