Lamotrigine (LTG), a new antiepileptic drug, requires long depolarizations to inhibit Na+ currents. This suggests either slow binding of LTG to the fast inactivated state or selective binding of LTG to the slow inactivated state of Na+ channels. To differentiate between these possibilities and to characterize further the action of LTG, we studied the affinity and kinetics of LTG binding to the Na+ channels in acutely dissociated hippocampal neurones of the rat.
LTG inhibited more Na+ currents at more depolarized holding potentials. The inhibitory effect at various holding potentials could be described by one-to-one binding curves, which yielded an apparent dissociation constant of ∼7μm for LTG binding to the inactivated channels (KI), and a dissociation constant more than 200 times larger for LTG binding to the resting channels. A similar value of KI (∼9μm) was also derived from the LTG concentration-dependent shift of the inactivation curve.
The recovery of LTG-bound inactivated Na+ channels was faster than the recovery of normal (drug-free) slow inactivated channels. Moreover, the binding kinetics of LTG onto the inactivated channels were faster than the development of the slow inactivated state, and were linearly correlated with LTG concentrations, with a binding rate constant of ∼10,000M−1s−1. These findings suggest that LTG chiefly binds to the fast inactivated state rather than the slow inactivated state.
We conclude that LTG, in therapeutic concentrations and at relatively depolarized membrane potentials, may potently inhibit Na+ currents by slow binding to the fast inactivated state of Na+ channels. Like phenytoin, the slow binding rates may explain why LTG effectively inhibits seizure discharges, yet spares most normal neuronal activities.