Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons.
The anticonvulsant phenytoin inhibited Na+ currents in rat hippocampal neurons with a potency that increased dramatically at depolarized holding potentials, suggesting weak binding to resting Na+ channels but tight binding to open or inactivated channels. Four different experimental measurements, i.e., steady block at different holding potentials, on and off kinetics at depolarized holding potentials, shifts in the inactivation curve, and dose-dependent slowing of recovery from inactivation, yielded an estimated Kd of approximately 7 microM for phenytoin binding to inactivated channels. Prolonged depolarizations of at least several seconds were necessary for significant block by therapeutic concentrations of phenytoin. The slow development of block does not reflect selective binding of phenytoin to slow inactivated states of the channel, because block developed faster and required less depolarized voltages than did slow inactivation. Instead, it appears that phenytoin binds tightly but slowly (approximately 10(4) M-1 sec-1) to fast inactivated states of the Na+ channels. This tight but slow binding may underlie the ability of phenytoin to disrupt epileptic discharges with minimal effects on normal firing patterns.
Kuo
C C
CC
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
Bean
B P
BP
D000818:Animals; D001665:Binding Sites; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D010672:Phenytoin / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism*
D015222:Sodium Channels; D010672:Phenytoin