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2019 - Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity

icon pl   Patchliner publication in CNS Neuroscience & Therapeutics (2019)

Authors:
Niespodziany I., Mullier B., André V.M., Ghisdal P., Jnoff E., Moreno‐Delgado D., Swinnen D., Sands Z., Wood M., Wolff C.

Journal:
CNS Neuroscience & Therapeutics (2019) 25: 442–451


Summary:

Aims

Kv1.1 (KCNA1) channels contribute to the control of neuronal excitability and have been associated with epilepsy. Kv1.1 channels can associate with the cytoplasmic Kvβ1 subunit resulting in rapid inactivating A‐type currents. We hypothesized that removal of channel inactivation, by modulating Kv1.1/Kvβ1 interaction with a small molecule, would lead to decreased neuronal excitability and anticonvulsant activity.

Methods

We applied high‐throughput screening to identify ligands able to modulate the Kv1.1‐T1 domain/Kvβ1 protein complex. We then selected a compound that was characterized on recombinant Kv1.1/Kvβ1 channels by electrophysiology and further evaluated on sustained neuronal firing and on in vitro epileptiform activity using a high K+‐low Ca2+ model in hippocampal slices.

Results

We identified a novel compound able to modulate the interaction of the Kv1.1/Kvβ1 complex and that produced a functional inhibition of Kv1.1/Kvβ1 channel inactivation. We demonstrated that this compound reduced the sustained repetitive firing in hippocampal neurons and was able to abolish the development of in vitro epileptiform activity.

Conclusions

This study describes a rational drug discovery approach for the identification of novel ligands that inhibit Kv1.1 channel inactivation and provides pharmacological evidence that such a mechanism translates into physiological effects by reducing in vitro epileptiform activity.


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