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

ABSTRACT:

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⁺

SUBMITTER: Niespodziany I 

PROVIDER: S-EPMC6488918 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature