Hu Hui-Juan, Carrasquillo Yarimar, Karim Farzana, Jung Wonil E, Nerbonne Jeanne M, Schwarz Thomas L, Gereau Robert W
Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Neuron. 2006 Apr 6;50(1):89-100. doi: 10.1016/j.neuron.2006.03.010.
A-type potassium currents are important determinants of neuronal excitability. In spinal cord dorsal horn neurons, A-type currents are modulated by extracellular signal-regulated kinases (ERKs), which mediate central sensitization during inflammatory pain. Here, we report that Kv4.2 mediates the majority of A-type current in dorsal horn neurons and is a critical site for modulation of neuronal excitability and nociceptive behaviors. Genetic elimination of Kv4.2 reduces A-type currents and increases excitability of dorsal horn neurons, resulting in enhanced sensitivity to tactile and thermal stimuli. Furthermore, ERK-mediated modulation of excitability in dorsal horn neurons and ERK-dependent forms of pain hypersensitivity are absent in Kv4.2(-/-) mice compared to wild-type littermates. Finally, mutational analysis of Kv4.2 indicates that S616 is the functionally relevant ERK phosphorylation site for modulation of Kv4.2-mediated currents in neurons. These results show that Kv4.2 is a downstream target of ERK in spinal cord and plays a crucial role in pain plasticity.
A型钾电流是神经元兴奋性的重要决定因素。在脊髓背角神经元中，A型电流受细胞外信号调节激酶（ERK）调控，ERK在炎性疼痛期间介导中枢敏化。在此，我们报告Kv4.2介导背角神经元中大部分的A型电流，并且是调节神经元兴奋性和伤害性感受行为的关键位点。基因敲除Kv4.2可减少A型电流并增加背角神经元的兴奋性，导致对触觉和热刺激的敏感性增强。此外，与野生型同窝小鼠相比，Kv4.2基因敲除小鼠中不存在ERK介导的背角神经元兴奋性调节以及ERK依赖性疼痛超敏反应形式。最后，Kv4.2的突变分析表明，S616是ERK在神经元中调节Kv4.2介导电流的功能相关磷酸化位点。这些结果表明，Kv4.2是脊髓中ERK的下游靶点，在疼痛可塑性中起关键作用。
