Effect of dextromethorphan on human K(v)1.3 channel activity: involvement of C-type inactivation

Abstract

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.