Efficacy loss of the anticonvulsant carbamazepine in mice lacking sodium channel beta subunits via paradoxical effects on persistent sodium currents

• Published in: The Journal of neuroscience Vol. 30; no. 25; pp. 8489 - 8501
• Main Authors: Uebachs, Mischa, Opitz, Thoralf, Royeck, Michel, Dickhof, Gesa, Horstmann, Marie-Therese, Isom, Lori L, Beck, Heinz
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 23.06.2010
• Subjects: Action Potentials - drug effects; Action Potentials - genetics; Animals; Anticonvulsants - pharmacology; Carbamazepine - pharmacology; Hippocampus - drug effects; Ion Channel Gating - drug effects; Ion Channel Gating - genetics; Membrane Potentials - drug effects; Membrane Potentials - genetics; Mice; Mice, Knockout; Neurons - drug effects; Patch-Clamp Techniques; Protein Subunits - genetics; Sodium Channels - genetics; Voltage-Gated Sodium Channel beta-1 Subunit
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1534-10.2010

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 alpha subunit and beta subunits, which modify the biophysical properties of alpha subunits. We have examined the idea that the presence of beta subunits also modifies the pharmacological properties of the Na(+) channel complex using mice lacking either the beta(1) (Scn1b) or beta(2) (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 beta 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 microm. 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, beta 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 beta subunits in other neurological disorders may cause altered neuronal sensitivity to drugs targeting Na(+) channels.