Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels.
Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels.
复制标题
DOI：
10.7554/elife.67914
复制
发表时间：
2021-05-11
期刊：
影响因子：
7.7
通讯作者：
Smith SM
中科院分区：
文献类型：
--
作者：
Martiszus BJ;Tsintsadze T;Chang W;Smith SM
细胞外[Ca²⁺]（[Ca²⁺]ₒ）升高会显著降低神经元的内在兴奋性，但其机制尚不清楚。一种假说认为，[Ca²⁺]ₒ屏蔽表面电荷，减少电压门控钠通道（VGSC）的激活；另一种假说则认为[Ca²⁺]ₒ激活钙敏感受体（CaSR），关闭钠泄漏通道（NALCN）。在此我们报道，与野生型（WT）相比，钙敏感受体缺陷型（Casr⁻/⁻）小鼠的新皮质神经元具有更负的静息电位，并且在含二价离子浓度降低的溶液（T0.2）中不会自发产生动作电位。然而，在将膜电位设定为 -70 mV后，T0.2的应用同样使Casr⁻/⁻和WT神经元去极化，并增加动作电位发放。VGSC的激活增强是T0.2引起去极化和兴奋性增加的主要原因，这是由于VGSC窗口电流的超极化位移所致。CaSR缺失使VGSC窗口电流去极化，但不影响NALCN的激活。外部二价离子对VGSC门控的调节是介导新皮质神经元兴奋性的二价离子依赖性变化的关键机制。
Increasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge, reducing voltage-gated sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) closing the sodium-leak channel (NALCN). Here we report that neocortical neurons from CaSR-deficient (Casr-/-) mice had more negative resting potentials and did not fire spontaneously in reduced divalent-containing solution (T0.2) in contrast with wild-type (WT). However, after setting membrane potential to −70 mV, T0.2 application similarly depolarized and increased action potential firing in Casr-/- and WT neurons. Enhanced activation of VGSCs was the dominant contributor to the depolarization and increase in excitability by T0.2 and occurred due to hyperpolarizing shifts in VGSC window currents. CaSR deletion depolarized VGSC window currents but did not affect NALCN activation. Regulation of VGSC gating by external divalents is the key mechanism mediating divalent-dependent changes in neocortical neuron excitability.