Potentiation of the Kv1 family K(+) channel by cortisone analogues.
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.
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, United States.
Yaping
Y
Pan
Elena J
EJ
Levin
Matthias
M
Quick
Ming
M
Zhou
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D003348:Cortisone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015195:Drug Design; D000068298:Fluticasone; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D051637:Shaker Superfamily of Potassium Channels / Q000819:agonists*; D054852:Small Molecule Libraries
D000305:Adrenal Cortex Hormones; D000730:Androstadienes; D051637:Shaker Superfamily of Potassium Channels; D054852:Small Molecule Libraries; D000068298:Fluticasone; D003348:Cortisone