Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity.
Action Potentials
/ drug effects
Animals
Dose-Response Relationship, Drug
Drug Discovery
/ methods
Female
HEK293 Cells
High-Throughput Screening Assays
/ methods
Hippocampus
/ drug effects
Humans
Kv1.1 Potassium Channel
/ agonists
Neurons
/ drug effects
Organ Culture Techniques
Potassium Channel Blockers
/ pharmacology
Protein Structure, Secondary
Rats
Xenopus laevis
electrophysiology
epilepsy
potassium channels
Journal
CNS neuroscience & therapeutics
ISSN: 1755-5949
Titre abrégé: CNS Neurosci Ther
Pays: England
ID NLM: 101473265
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
07
06
2018
revised:
13
08
2018
accepted:
15
08
2018
pubmed:
23
9
2018
medline:
12
9
2020
entrez:
23
9
2018
Statut:
ppublish
Résumé
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. 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 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. 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.
Identifiants
pubmed: 30242974
doi: 10.1111/cns.13060
pmc: PMC6488918
doi:
Substances chimiques
Potassium Channel Blockers
0
Kv1.1 Potassium Channel
147173-20-4
Banques de données
GENBANK
['NM_000217', 'NM_172160', 'NM_002233']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
442-451Informations de copyright
© 2018 John Wiley & Sons Ltd.
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