Efficacy Loss of the Anticonvulsant Carbamazepine in Mice Lacking Sodium Channel β Subunits via Paradoxical Effects on Persistent Sodium Currents

摘要

Neuronal excitability is critically determined by the properties of voltage-gated Na⁺ currents. Fast transient Na⁺ currents (INaT) mediate the fast upstroke of action potentials, whereas low-voltage-activated persistent Na⁺ currents (INaP) contribute to subthreshold excitation. Na⁺ channels are composed of a pore-forming α subunit and β subunits, which modify the biophysical properties of α subunits. We have examined the idea that the presence of β subunits also modifies the pharmacological properties of the Na⁺ channel complex using mice lacking either the β1 (Scn1b) or β2 (Scn2b) subunit. Classical effects of the anticonvulsant carbamazepine (CBZ), such as the use-dependent reduction of INaT and effects on INaT voltage dependence of inactivation, were unaltered in mice lacking β subunits. Surprisingly, CBZ induced a small but significant shift of the voltage dependence of activation of INaT and INaP to more hyperpolarized potentials. This novel CBZ effect on INaP was strongly enhanced in Scn1b null mice, leading to a pronounced increase of INaP within the subthreshold potential range, in particular at low CBZ concentrations of 10–30 μm. A combination of current-clamp and computational modeling studies revealed that this effect causes a complete loss of CBZ efficacy in reducing repetitive firing. Thus, β subunits modify not only the biophysical but also the pharmacological properties of Na⁺ channels, in particular with respect to INaP. Consequently, altered expression of β subunits in other neurological disorders may cause altered neuronal sensitivity to drugs targeting Na⁺ channels.