Abstract

Neuronal excitability is critically determined by the properties of voltage-gated Na⁺ currents. Fast transient Na⁺ currents (I_NaT) mediate the fast upstroke of action potentials, whereas low-voltage-activated persistent Na⁺ currents (I_NaP) 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 I_NaT and effects on I_NaT 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 I_NaT and I_NaP to more hyperpolarized potentials. This novel CBZ effect on I_NaP was strongly enhanced in Scn1b null mice, leading to a pronounced increase of I_NaP 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 I_NaP. Consequently, altered expression of β subunits in other neurological disorders may cause altered neuronal sensitivity to drugs targeting Na⁺ channels.