Efficacy loss of the anticonvulsant carbamazepine in mice lacking sodium channel beta subunits via paradoxical effects on persistent sodium currents.
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.
Uebachs
Mischa
M
Department of Epileptology, University of Bonn Medical Center, 53105 Bonn, Germany.
Opitz
Thoralf
T
Royeck
Michel
M
Dickhof
Gesa
G
Horstmann
Marie-Therese
MT
Isom
Lori L
LL
Beck
Heinz
H
D000200:Action Potentials / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
D000927:Anticonvulsants; D021122:Protein Subunits; C524974:Scn1b protein, mouse; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D002220:Carbamazepine