ACTIVATION OF CYCLIN-DEPENDENT KINASE 5 BROADENS ACTION POTENTIALS IN HUMAN SENSORY NEURONS.
ACTIVATION OF CYCLIN-DEPENDENT KINASE 5 BROADENS ACTION POTENTIALS IN HUMAN SENSORY NEURONS.
复制标题
周期蛋白依赖性激酶 5 的激活扩大了人类感觉神经元的动作电位。
DOI：
10.1101/2023.05.31.543017
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kulkarni,AshokB
中科院分区：
文献类型：
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作者：
Tiwari,ManindraNath;Hall,BradfordE;Terse,Anita;Amin,Niranjana;Chung,Man-Kyo;Kulkarni,AshokB
慢性疼痛是最具破坏性和最令人不快的疾病之一，与许多病理状态有关。组织或神经损伤在伤害性神经元中诱导广泛的神经生物学可塑性，从而导致慢性疼痛。最近的研究表明，初级传入神经元中的细胞周期蛋白依赖性激酶5(CDK5)是一种关键的神经元激酶，在病理条件下通过磷酸化来调节伤害性感受。然而，CDK5对伤害性感受器活动的影响，特别是对人类感觉神经元的影响尚不清楚。为了确定CDK5对人背根神经节(HDRG)神经元特性的调节，我们在分离的hDRG神经元上进行了全细胞膜片钳记录。与对照神经元相比，p35过表达引起的CDK5激活使静息膜电位去极化，并降低了电流。激活CDK5可通过延长动作电位的上升时间、下降时间和半宽度改变动作电位的形状。应用前列腺素E_2(PG)和缓激肽(BK)混合液控制hDRG神经元，可引起RMP去极化，并随着AP上升时间的延长而使流变基电流减少。然而，PG和BK应用未能在p35过表达组中诱导任何显著的变化。我们的结论是，在分离的hDRGs神经元中，通过p35的过度表达激活CDK5可以扩大AP，并且CDK5可能在CDK5上调的情况下在调节人类初级传入神经元的AP属性中发挥重要作用，从而导致慢性疼痛。
Chronic pain is one of the most devastating and unpleasant conditions, associated with many pathological states. Tissue or nerve injuries induce extensive neurobiological plasticity in nociceptive neurons, which leads to chronic pain. Recent studies suggest that cyclin-dependent kinase 5 (CDK5) in primary afferents is a key neuronal kinase that modulates nociception through phosphorylation under pathological conditions. However, the impact of the CDK5 on nociceptor activity especially in human sensory neurons is not known. To determine the CDK5-mediated regulation of human dorsal root ganglia (hDRG) neuronal properties, we have performed the whole-cell patch clamp recordings in neurons dissociated from hDRG. CDK5 activation induced by overexpression of p35 depolarized the resting membrane potential (RMP) and reduced the rheobase currents as compared to the control neurons. CDK5 activation changed the shape of the action potential (AP) by increasing AP -rise time, -fall time, and -half width. The application of a prostaglandin E2 (PG) and bradykinin (BK) cocktail in control hDRG neurons induced the depolarization of RMP and the reduction of rheobase currents along with increased AP rise time. However, PG and BK applications failed to induce any significant changes in the p35-overexpressing group. We conclude that, in dissociated hDRGs neurons, CDK5 activation through the overexpression of p35 broadens the AP and that CDK5 may play important roles in the modulation of AP properties in human primary afferents under the condition in which CDK5 is upregulated, contributing to chronic pain.