Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity
| Autor: | Zara A. Sands, Brice Mullier, Isabelle Niespodziany, Eric Jnoff, David Moreno-Delgado, Christian Wolff, Dominique Swinnen, Véronique M. André, Philippe Ghisdal, Martyn Wood |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Protein subunit medicine.medical_treatment Action Potentials Hippocampal formation complex mixtures Hippocampus Protein Structure Secondary 03 medical and health sciences Xenopus laevis 0302 clinical medicine Organ Culture Techniques Physiology (medical) Drug Discovery medicine Potassium Channel Blockers Animals Humans Pharmacology (medical) Pharmacology Neurons Dose-Response Relationship Drug Chemistry Drug discovery Original Articles Small molecule In vitro Potassium channel High-Throughput Screening Assays Rats Psychiatry and Mental health Electrophysiology 030104 developmental biology Anticonvulsant HEK293 Cells nervous system Biophysics Female Kv1.1 Potassium Channel 030217 neurology & neurosurgery |
| Zdroj: | CNS neurosciencetherapeutics. 25(4) |
| ISSN: | 1755-5949 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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