Anticonvulsant phenytoin affects voltage-gated potassium currents in cerebellar granule cells

The anticonvulsant drug phenytoin (diphenylhydantoin, DPH) was examined for its action on potassium currents in cerebellar granule cells using the whole-cell patch-clamp technique. Granular cells expressed two main types of voltage-dependent potassium currents: the first, sensitive to Tetraethylammonium ion (TEA), resembles a delayed rectifier K(+) channel (I (d)); the second shows biophysical and pharmacological properties similar to an I(A)-type potassium current. Phenytoin blocks the I(A) current in a dose-dependent manner, with an apparent dissociation constant K(d) of (73+/-7) microM. The drug shifts the steady-state inactivation curves towards a more negative potential, stabilizing the inactivated state, while the activation kinetics remain unaffected. The estimated K(d) when the cell is held to -100 mV (closed state of the channel) is 145+/-8 microM which decreases to 35+/-10 microM at -80 mV holding potential (partial inactivation of the channel). Phenytoin shows a discriminant behaviour between the two different types of potassium channels because at high concentration the effect of the drug on the delayed rectifier K(+) channel is negligible.