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[摘要]：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 (Kv beta), some of which inhibit channel activity. Cortisone potentiates Kv1 channel by binding to Kv beta and promoting its dissociation from the channel, but its half-maximum effective concentration is similar to 46 mu M. 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 (EC50) of 37 +/- 1.1 nM. Further studies showed that fluticasone propionate potentiates channel current by inducing dissociation of Kv beta, and docking of fluticasone propionate into the cortisone binding propionate site reveals potential interactions that enhance the EC50 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-Kv beta complex. |
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