Differential effects of blockade of ERG channels on gamma oscillations and excitability in rat hippocampal slices.
Agents such as sertindole and astemizole affect heart action by inducing long-QT syndrome, suggesting that apart from their neuronal actions through histamine receptors, 5-HT2 serotonin receptors and D2 dopamine receptors they also affect ether-a-go-go channels and particularly ether-a-go-go-related (ERG) potassium (K(+)) channels, comprising the K(v) 11.1, K(v) 11.2 and K(v) 11.3 voltage-gated potassium currents. Changes in ERG K(+) channel expression and activity have been reported and may be linked to schizophrenia [Huffaker, S.J., Chen, J., Nicodemus, K.K., Sambataro, F., Yang, F., Mattay, V., Lipska, B.K., Hyde, T.M., Song, J., Rujescu, D., Giegling, I., Mayilyan, K., Proust, M.J., Soghoyan, A., Caforio, G., Callicott, J.H., Bertolino, A., Meyer-Lindenberg, A., Chang, J., Ji, Y., Egan, M.F., Goldberg, T.E., Kleinman, J.E., Lu, B. & Weinberger DR. (2009). Nat. Med., 15, 509-518; Shepard, P.D., Canavier, C.C. & Levitan, E.S. (2007). Schizophr Bull., 33, 1263-1269]. We have previously shown that histamine H1 blockers augment gamma oscillations (γ) which are thought to be involved in cognition and storage of information. These effects were particularly pronounced for γ induced by acetylcholine. Here we have compared neuronal effects of three agents which interfere with ERG K(+) channels. We found that astemizole and sertindole, but not the K(v) 11 channel blocker E4031, augmented γ induced by acetylcholine in hippocampal slices. Kainate-induced γ were only affected by astemizole. Evoked responses induced by stratum radiatum stimulation in area CA1 revealed that only E4031 augmented stimulus-induced synaptic potentials and neuronal excitability. Our findings suggest that K(v) 11 channels are involved in neuronal excitability without clear effects on γ and that the effect of astemizole is related to actions on H1 receptors.
Institute for Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Silvia
S
Fano
Gürsel
G
Çalışkan
Uwe
U
Heinemann
D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016589:Astemizole / Q000494:pharmacology; D058256:Brain Waves / Q000187:drug effects*; D056547:CA1 Region, Hippocampal / Q000502:physiology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D055366:Synaptic Potentials / Q000187:drug effects
D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; D007211:Indoles; D026902:Potassium Channel Blockers; D016589:Astemizole; C066304:sertindole; D000109:Acetylcholine; D007608:Kainic Acid