A discriminant block among K⁺ channel types by phenytoin in neuroblastoma cells

Abstract

1 The action of the anticonvulsant drug phenytoin on K + channels was investigated in neuroblastoma cells (N2A) by using the single-channel patch-clamp technique. 2 N2A cells expressed three types of delayed recti®er K + channels, which were found to have a conductance of 10 ± 20 pS in a`physiological' K + gradient. When added to the external solution at concentrations ranging between 1 and 200 mM, phenytoin decreased single channel activity, whereas the unitary current amplitude was una ected in all three types of channels. 3 The open probability of the biggest channel decreased, according to an exponential distribution of open and closed times, from 40% in control conditions to 10% in the presence of 50 mM phenytoin (Vm=40 mv). The reduction in the open-channel probability was concentration-dependent with a IC 50 =27.2+0.9 mM. 4 A transient type of K + channel was identi®ed that was a ected by cumulative inactivation and had a conductance of a mean value equal to 26 pS. Finally, a voltage-and Ca 2+ -dependent K + channel with a unitary conductance of 95 pS was recorded. Both the channel's amplitude and kinetics were una ected by phenytoin. 5 These results con®rm the phenytoin e ect on K + currents and suggest that the drug may be considered a selective blocker of delayed recti®er K + channels.

The cognition‐enhancing activity of E1R, a novel positive allosteric modulator of sigma‐1 receptors

“…Apart from E1R, few positive allosteric modulators of sigma‐1 receptors have been described (Cobos et al ., ; Guo et al ., ). Phenytoin has been reported to decrease motor activity in mice (Poncelet et al ., ), reduce increases in extracellular K + concentrations (Nobile and Lagostena, ) and inhibit both Na + (Rush and Elliott, ) and T‐type Ca 2+ currents (Todorovic and Lingle, ). Unlike E1R, treatment with phenytoin triggered memory impairment during the PA task (Reeta et al ., ).…”

Allosteric Modulators of Sigma-1 Receptor: A Review

“…The mechanism by which phenytoin exerts its anti-seizure activity is primarily related to the inhibition of voltage-gated sodium channels (Tunnicliff, 1996 ). Phenytoin has been reported to reduce increases in extracellular K + concentration in neuroblastoma cells (Nobile and Lagostena, 1998 ) and inhibit both Na + (Rush and Elliott, 1997 ) and T-type Ca 2+ currents in isolated dorsal root ganglia (Todorovic and Lingle, 1998 ). Phenytoin was shown to block the decrease in extracellular Ca 2+ concentration effected by repetitive stimulation of pyramidal cells in hippocampal slices (Yaari et al, 1986 ).…”

Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited

“…Although, modulation of potassium channels would seem to be an ideal target for AEDs, most drugs have no or poorly characterized effects on potassium channels. However, phenytoin blocks the delayed rectifier potassium channels in neuroblastoma cells and retigabine, a putative AED, has as its main mode of action potentiation of potassium M-type channels [Wuttke et al 2005;Tatulian et al 2001;Nobile and Lagostena, 1998]. …”