FIGURE 24–2 (A1) Voltage-gated sodium channels mediate the upstroke of action potentials in brain neurons. Fast inactivation of sodium channels (along with the activation of potassium channels) terminates the action potential. (A2) Voltage-clamp recording of sodium channel current following depolarization, illustrating the time course of sodium channel gating. (B) Schematic illustration of the voltage-dependent gating of sodium channels between closed, open, and inactivated states. (C1) Primary structures of the subunits of sodium channels. The main α subunit, consisting of four homologous repeats (I–IV), is shown flanked by the two auxiliary β subunits. Cylinders represent α-helical transmembrane segments. Blue α-helical segments (S5, S6) form the pore region. +, S4 voltage sensors; grey circles, inactivation particle in inactivation gate loop; III-S6 and IV-S6 (red) are regions of antiseizure drug binding. (C2) Schematic illustration of the sodium channel pore composed of the homologous repeats arrayed around the central channel pore through which sodium flows into the neuron. The S5 and S6 transmembrane α-helical segments from each homologous repeat (I–IV) form the four walls of the pore. The outer pore mouth and ion selectivity filter are formed by re-entrant P-loops. The key α-helical S6 segments in repeat III and IV, which contain the antiseizure drug binding sites, are highlighted. A lamotrigine molecule is illustrated in association with its binding site.
B Voltage Dependence of Block Use Dependence of Block 100Percent of ControlNormalized Current 50 –90 mV –60 mV 0 –90 mV –60 mV 0 mV 1 ms 1 nA 1.0 0.5 0.0 1.0 0.5 0.0 0 5 10 Control 0.7 ms pulse duration 20 ms pulse duration Lamotrigine 15 20 55 60
FIGURE 24–3 (A) Selective effect of a clinically relevant concentration of lamotrigine (50 μM) on action potentials and epileptic-like discharges in rat hippocampal neurons as assessed with intracellular recording. In normal recording conditions, lamotrigine has no effect on action potentials or on the evoked excitatory postsynaptic potentials (EPSPs) that elicit the action potential. In epileptic-like conditions (low magnesium), activation elicits initial spikes followed by repetitive epileptiform spike firing (afterdischarge). Lamotrigine inhibits the pathologic discharge but not the initial spikes. EPSPs were elicited by stimulation of the Schaffer collateral/commissural fibers (triangles).