Functional Genomics Section, National Institute of Dental and Craniofacial Research.
Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Mol Pain. 2017 Jan-Dec;13:1744806917737205. doi: 10.1177/1744806917737205.
Cdk5 is a key neuronal kinase necessary for proper brain development, which has recently been implicated in modulating nociception. Conditional deletion of Cdk5 in pain-sensing neurons attenuates pain responses to heat in both the periphery and orofacial regions. Cdk5 activity is regulated by binding to the activators p35 and p39, both of which possess a cyclin box. Our previous examination of the nociceptive role of the well-characterized Cdk5 activator p35 using mice that either lack or overexpress this regulatory subunit demonstrated that Cdk5/p35 activity affects mechanical, chemical, and thermal nociception. In contrast, the nociceptive role of Cdk5’s other less-studied activator p39 is unknown. Here, we report that the knockout of p39 in mice did not affect orofacial and peripheral nociception. The lack of any algesic response to nociceptive stimuli in the p39 knockout mice contrasts with the hypoalgesic effects that result from the deletion of p35. Our data demonstrate different and nonoverlapping roles of Cdk5 activators in the regulation of orofacial as well as peripheral nociception with a crucial role for Cdk5/p35 in pain signaling.
Cdk5 是一种关键的神经元激酶，对于大脑的正常发育是必需的，它最近被牵涉到调节伤害感受。在痛觉感受神经元中条件性敲除 Cdk5 可减弱外周和口腔区域对热的痛觉反应。Cdk5 的活性通过与激活剂 p35 和 p39 的结合来调节，这两种激活剂都具有细胞周期蛋白盒。我们之前使用缺乏或过表达这种调节亚基的小鼠对疼痛作用明确的 Cdk5 激活剂 p35 进行了研究，结果表明 Cdk5/p35 活性影响机械、化学和热伤害感受。相比之下，Cdk5 的另一种研究较少的激活剂 p39 的疼痛作用尚不清楚。在这里，我们报告说，p39 在小鼠中的敲除不会影响口腔和外周伤害感受。与 p35 缺失导致的镇痛效应相反，p39 敲除小鼠对伤害性刺激没有任何痛觉反应。我们的数据表明，Cdk5 激活剂在口腔和外周伤害感受的调节中具有不同且不重叠的作用，Cdk5/p35 在疼痛信号传递中起着关键作用。
