Cinacalcet inhibition of neuronal action potentials preferentially targets the fast inactivated state of voltage-gated sodium channels.
Cinacalcet inhibition of neuronal action potentials preferentially targets the fast inactivated state of voltage-gated sodium channels.
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DOI：
10.3389/fphys.2022.1066467
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发表时间：
2022
影响因子：
4
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中科院分区：
文献类型：
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电压门控钠通道（VGSC）激活对于脑中动作电位的产生是必不可少的。别构钙敏感受体（CaSR）激动剂西那卡塞通过一种未鉴定的G蛋白依赖性抑制分子强烈且普遍地抑制新皮层神经元中的VGSC电流。在这里，使用全细胞膜片钳方法，我们研究了西那卡塞介导的VGSC抑制的电压依赖性和西那卡塞的通道状态偏好。VGSC电流的抑制率在更多的去极化保持电位加速。西那卡塞使VGSC电流的快速和缓慢失活的电压依赖性向超极化方向移动。利用一个简单的模型，VGSC电流抑制的电压依赖性可以解释，如果抑制分子的亲和力通道状态遵循的顺序：快速失活>缓慢失活>休息。VGSC电流抑制的状态依赖性导致西那卡塞动作电位阻滞的非线性。西那卡塞调节VGSC电流的这种动态和丰富的信号通路为调节中枢神经元兴奋性提供了重要的电压依赖性机制。
Voltage-gated sodium channel (VGSC) activation is essential for action potential generation in the brain. Allosteric calcium-sensing receptor (CaSR) agonist, cinacalcet, strongly and ubiquitously inhibits VGSC currents in neocortical neurons via an unidentified, G-protein-dependent inhibitory molecule. Here, using whole-cell patch VGSC clamp methods, we investigated the voltage-dependence of cinacalcet-mediated inhibition of VGSCs and the channel state preference of cinacalcet. The rate of inhibition of VGSC currents was accelerated at more depolarized holding potentials. Cinacalcet shifted the voltage-dependence of both fast and slow inactivation of VGSC currents in the hyperpolarizing direction. Utilizing a simple model, the voltage-dependence of VGSC current inhibition may be explained if the affinity of the inhibitory molecule to the channel states follows the sequence: fast-inactivated > slow-inactivated > resting. The state dependence of VGSC current inhibition contributes to the non-linearity of action potential block by cinacalcet. This dynamic and abundant signaling pathway by which cinacalcet regulates VGSC currents provides an important voltage-dependent mechanism for modulating central neuronal excitability.
影响因子：
4.6
作者：
Cervenka R;Lukacs P;Gawali VS;Ke S;Koenig X;Rubi L;Zarrabi T;Hilber K;Sandtner W;Stary-Weinzinger A;Todt H
通讯作者：
Todt H