Potentiation of the Kv1 Family K+ Channel by Cortisone Analogues
Autor: | Elena J. Levin, Yaping Pan, Matthias Quick, Ming Zhou |
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Rok vydání: | 2012 |
Předmět: |
Models
Molecular Stereochemistry Biochemistry Article Fluticasone propionate Small Molecule Libraries Adrenal Cortex Hormones medicine Humans Myocyte Binding site Fluticasone Binding Sites Chemistry Rational design Long-term potentiation General Medicine Androstadienes Cortisone HEK293 Cells Docking (molecular) Drug Design Shaker Superfamily of Potassium Channels Molecular Medicine medicine.drug |
Zdroj: | ACS Chemical Biology. 7:1641-1646 |
ISSN: | 1554-8937 1554-8929 |
Popis: | The Kv1 family voltage-dependent K(+) channels are essential for termination of action potentials in neurons and myocytes. These channels form a stable complex with their beta subunits (Kvβ), some of which inhibit channel activity. Cortisone potentiates Kv1 channel by binding to Kvβ and promoting its dissociation from the channel, but its half-maximum effective concentration is ∼46 μM. To identify corticosteroids that are more efficient than cortisone, we examined 25 cortisone analogues and found that fluticasone propionate potentiates channel current with a half-maximum effective concentration (EC(50)) of 37 ± 1.1 nM. Further studies showed that fluticasone propionate potentiates channel current by inducing dissociation of Kvβ, and docking of fluticasone propionate into the cortisone binding site reveals potential interactions that enhance the EC(50) value. Thus, fluticasone propionate provides a starting point for rational design of more efficient small-molecule compounds that increase Kv1 activity and affect the integrity of the Kv1-Kvβ complex. |
Databáze: | OpenAIRE |
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