Department of Pharmacology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Eur J Pharmacol. 2011 Jan 25;651(1-3):122-7. doi: 10.1016/j.ejphar.2010.10.091. Epub 2010 Nov 27.
Dextromethorphan exhibits neuroprotective effects against inflammation-mediated neurodegeneration. However, relatively little is known regarding the molecular mechanism for this inflammation-mediated neuroprotection. Human K(v)1.3 channels, one of the voltage-gated potassium channels, are widely expressed in the immune and nervous systems. Activation of human K(v)1.3 channels causes neuroglia-mediated neurodegeneration. Agents that inhibit human K(v)1.3 channel activity have been developed as novel drugs for immunosuppression. In the present study, we investigated the effects of dextromethorphan on human K(v)1.3 or K(v)1.2 channel activity heterologously expressed in Xenopus laevis oocytes. The channel currents were measured with the two-electrode voltage clamp technique. Activation of both channels induced outward peak and steady-state currents. Dextromethorphan treatment induced a slight inhibition of peak currents in human K(v)1.2 and K(v)1.3 channels, whereas dextromethorphan profoundly inhibited the steady-state currents of human K(v)1.3 channels compared to K(v)1.2 channel currents. Dextromethorphan's action on steady-state currents of human K(v)1.3 channels was in a concentration-dependent manner. The half-maximal inhibitory concentration (IC(50)) on steady-state currents of human K(v)1.3 channels was 12.8±1.6μM. Dextromethorphan also accelerated the C-type inactivation rate, increased the current decay rate, and inhibited currents in a use-dependent manner. These results indicate that dextromethorphan accelerates C-type inactivation of human K(v)1.3 channels and acts as an open-channel blocker. These results further suggest the possibility that dextromethorphan-mediated acceleration of C-type inactivation of human K(v)1.3 channels might be one of the cellular bases of dextromethorphan-mediated protection against inflammation-mediated neurodegeneration.
右美沙芬表现出对炎症介导的神经退行性变的神经保护作用。然而，对于这种炎症介导的神经保护作用的分子机制，人们知之甚少。人 K(v)1.3 通道是人电压门控钾通道之一，广泛表达于免疫和神经系统。人 K(v)1.3 通道的激活会导致神经胶质介导的神经退行性变。抑制人 K(v)1.3 通道活性的药物已被开发为新型免疫抑制剂。在本研究中，我们研究了右美沙芬对在非洲爪蟾卵母细胞中异源表达的人 K(v)1.3 或 K(v)1.2 通道活性的影响。采用双电极电压钳技术测量通道电流。两种通道的激活均诱导外向峰和稳态电流。右美沙芬处理轻微抑制了人 K(v)1.2 和 K(v)1.3 通道的峰电流，而与 K(v)1.2 通道电流相比，右美沙芬显著抑制了人 K(v)1.3 通道的稳态电流。右美沙芬对人 K(v)1.3 通道稳态电流的作用呈浓度依赖性。对人 K(v)1.3 通道稳态电流的半数最大抑制浓度 (IC(50)) 为 12.8±1.6μM。右美沙芬还加速 C 型失活速率，增加电流衰减速率，并以使用依赖性方式抑制电流。这些结果表明，右美沙芬加速了人 K(v)1.3 通道的 C 型失活，并作为一种开放通道阻断剂。这些结果进一步表明，右美沙芬介导的人 K(v)1.3 通道 C 型失活的加速可能是人 K(v)1.3 通道 C 型失活介导的对炎症介导的神经退行性变的保护作用的细胞基础之一。
