Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan.
J Theor Biol. 2009 Aug 21;259(4):828-36. doi: 10.1016/j.jtbi.2009.05.003. Epub 2009 May 14.
The rapidly inactivating (I(Naf)) and noninactivating Na(+) currents (I(Na)(()(NI)())) were characterized in NG108-15 neuronal cells differentiated with dibutyryl cyclic AMP in this study. Standard activation and inactivation protocols were used to evaluate the steady-state and kinetic properties of the I(Naf) present in these cells. The voltage protocols with a slowly depolarizing ramp were implemented to examine the properties of I(Na)(()(NI)()). Based on experimental data and computer simulations, a window component of the rapidly inactivating sodium current (I(Naf)(()(W)())) was also generated in response to the slowly depolarizing ramp. The I(Naf)(()(W)()) was subtracted from I(Na)(()(NI)()) to yield the persistent Na(+) current (I(Na)(()(P)())). Our results demonstrate the presence of I(Na)(()(P)()) in these cells. In addition to modifying the steady-state inactivation of I(Naf), ranolazine or riluzloe could be effective in blocking I(Naf)(()(W)()) and I(Na)(()(P)()). The ability of ranolazine and riluzole to suppress I(Na)(()(P)()) was greater than their ability to inhibit I(Naf)(()(W)()). In current-clamp recordings, current-induced voltage oscillations were applied to elicit action potentials (APs) through a gradual transition between spontaneous depolarization and upstroke. Ranolazine or riluzole at a concentration of 3 microM then effectively suppressed the AP firing generated by oscillatory changes in membrane current. The data suggest that a small rise in I(Na)(()(NI)()) facilitates neuronal hyper-excitability due the decreased threshold of AP initiation. The underlying mechanism of the inhibitory actions of ranolazine or riluzole on membrane potential in neurons or neuroendocrine cells in vivo may thus be associated with their blocking of I(Na)(()(NI)()).
在本研究中，我们使用二丁酰环腺苷酸（dbcAMP）将 NG108-15 神经元细胞分化，以研究快速失活（I（Naf））和非失活 Na+电流（I（Na）（（（NI））））。我们使用标准激活和失活方案来评估存在于这些细胞中的 I（Naf）的稳态和动力学特性。通过实施具有缓慢去极化斜坡的电压方案，研究 I（Na）（（（NI）））的特性。根据实验数据和计算机模拟，还针对缓慢去极化斜坡生成了快速失活钠电流（I（Naf）（（（W）））的窗口分量。从 I（Na）（（（NI）））中减去 I（Naf）（（（W））），得到持续的 Na+电流（I（Na）（（（P））））。我们的结果表明这些细胞中存在 I（Na）（（（P）））。除了改变 I（Naf）的稳态失活外，雷诺嗪或利鲁唑还可以有效阻断 I（Naf）（（（W）））和 I（Na）（（（P）））。雷诺嗪和利鲁唑抑制 I（Na）（（（P）））的能力大于抑制 I（Naf）（（（W）））的能力。在电流钳记录中，施加电流诱导的电压振荡，通过自发性去极化和上升之间的逐渐过渡来引发动作电位（AP）。然后，浓度为 3μM 的雷诺嗪或利鲁唑有效抑制了由膜电流振荡变化引起的 AP 放电。数据表明，由于 AP 起始阈值降低，I（Na）（（（NI）））的微小增加促进了神经元的过度兴奋。因此，雷诺嗪或利鲁唑对体内神经元或神经内分泌细胞的膜电位的抑制作用的潜在机制可能与其对 I（Na）（（（NI）））的阻断作用有关。
