Mechanisms of calcium channel block by phenytoin.
One of the proposed anticonvulsant actions of phenytoin (5,5'-diphenylhydantoin) is the suppression of calcium movement through cell membranes. However, it is not known how phenytoin interacts with calcium channels to inhibit calcium accumulation in various preparations, or to interfere with calcium-dependent neurotransmitter release. The objective of the present study was to examine whether phenytoin directly blocks voltage-dependent calcium channels of N1E-115 neuroblastoma, and if so, to determine what properties of channel gating are modified by this anticonvulsant. Calcium channel currents as carried by barium were recorded with the whole-cell voltage clamp technique. Low-threshold, transient currents ("type I") were activated at membrane potentials more positive than -50 mV. Type I currents were of maximum amplitude at -20 or -10 mV. High-threshold, sustained currents ("type II") were activated at potentials more positive than -10 mV. Application of phenytoin, at concentrations ranging from 3 to 100 microM, suppressed type I currents without changing their time course or voltage dependence of activation. Type II currents, on the other hand, were insensitive to phenytoin within this concentration range. The block of type I currents by phenytoin was enhanced when the membrane was maintained at more depolarized holding potentials, due to a hyperpolarizing shift in the steady-state inactivation relationship. In addition to the "resting block" of type I channels, phenytoin exerted an additional component of blocking at stimulation frequencies higher than 0.5 Hz. These voltage- and frequency-dependent blocking actions suggest that phenytoin shifts the channel population toward the inactivated state, allowing fewer channels to open during membrane depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)
Twombly
D A
DA
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois.
Yoshii
M
M
Narahashi
T
T
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D007473:Ion Channels / Q000187:drug effects*; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology*
D007473:Ion Channels; D010672:Phenytoin; D002118:Calcium