Clinical Research Center of Neurological Disease & Department of Geriatrics, The Second Affiliated Hospital of Soochow University, 1055 San-Xiang Road, Suzhou, 215004, People's Republic of China.
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, People's Republic of China.
J Headache Pain. 2023 Aug 25;24(1):117. doi: 10.1186/s10194-023-01658-2.
Adipokines, including adiponectin, are implicated in nociceptive pain; however, the underlying cellular and molecular mechanisms remain unknown.
Using electrophysiological recording, immunostaining, molecular biological approaches and animal behaviour tests, we elucidated a pivotal role of adiponectin in regulating membrane excitability and pain sensitivity by manipulating Cav3.2 channels in trigeminal ganglion (TG) neurons.
Adiponectin enhanced T-type Ca channel currents (I) in TG neurons through the activation of adiponectin receptor 1 (adipoR1) but independently of heterotrimeric G protein-mediated signaling. Coimmunoprecipitation revealed a physical association between AdipoR1 and casein kinase II alpha-subunits (CK2α) in the TG, and inhibiting CK2 activity by chemical inhibitor or siRNA targeting CK2α prevented the adiponectin-induced I response. Adiponectin significantly activated protein kinase C (PKC), and this effect was abrogated by CK2α knockdown. Adiponectin increased the membrane abundance of PKC beta1 (PKCβ1). Blocking PKCβ1 pharmacologically or genetically abrogated the adiponectin-induced I increase. In heterologous expression systems, activation of adipoR1 induced a selective enhancement of Cav3.2 channel currents, dependent on PKCβ1 signaling. Functionally, adiponectin increased TG neuronal excitability and induced mechanical pain hypersensitivity, both attenuated by T-type channel blockade. In a trigeminal neuralgia model induced by chronic constriction injury of infraorbital nerve, blockade of adipoR1 signaling suppressed mechanical allodynia, which was prevented by silencing Cav3.2.
Our study elucidates a novel signaling cascade wherein adiponectin stimulates TG Cav3.2 channels via adipoR1 coupled to a novel CK2α-dependent PKCβ1. This process induces neuronal hyperexcitability and pain hypersensitivity. Insight into adipoR-Cav3.2 signaling in sensory neurons provides attractive targets for pain treatment.
脂肪细胞因子，包括脂联素，与伤害感受性疼痛有关；然而，其潜在的细胞和分子机制尚不清楚。
我们通过操纵三叉神经节（TG）神经元中的 Cav3.2 通道，利用电生理记录、免疫染色、分子生物学方法和动物行为测试，阐明了脂联素通过激活脂联素受体 1（adipoR1）在调节膜兴奋性和痛觉敏感性方面的关键作用。
脂联素通过激活 adipoR1 增强了 TG 神经元中的 T 型钙通道电流（I），但不依赖于异三聚体 G 蛋白介导的信号转导。共免疫沉淀显示，在 TG 中，AdipoR1 与酪蛋白激酶 IIα 亚基（CK2α）之间存在物理关联，通过化学抑制剂或靶向 CK2α 的 siRNA 抑制 CK2 活性可阻止脂联素诱导的 I 反应。脂联素显著激活蛋白激酶 C（PKC），而 CK2α 敲低可消除这种作用。脂联素增加了 PKCβ1（PKCβ1）的膜丰度。用药物或基因阻断 PKCβ1 可消除脂联素诱导的 I 增加。在异源表达系统中，adipoR1 的激活可选择性增强 Cav3.2 通道电流，这依赖于 PKCβ1 信号转导。功能上，脂联素增加了 TG 神经元的兴奋性，并诱导机械性痛觉过敏，这两种作用均被 T 型通道阻断所减弱。在眶下神经慢性缩窄损伤诱导的三叉神经痛模型中，adipoR1 信号阻断抑制了机械性痛觉过敏，而 Cav3.2 的沉默则阻止了这种作用。
我们的研究阐明了一条新的信号级联，其中脂联素通过 adipoR1 刺激 TG Cav3.2 通道，该通道与一种新型的 CK2α 依赖的 PKCβ1 偶联。这一过程导致神经元过度兴奋和痛觉过敏。对感觉神经元中 adipoR-Cav3.2 信号的深入了解为疼痛治疗提供了有吸引力的靶点。
