Potentiation of the Kv1 Family K+ Channel by Cortisone Analogues
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- 作者：Yaping Pan ; Elena J. Levin ; Matthias Quick ; Ming Zhou
- 刊名：ACS Chemical Biology
- 出版年：2012
- 出版时间：October 19, 2012
- 年：2012
- 卷：7
- 期：10
- 页码：1641-1646
- 全文大小：378K
- 年卷期：v.7,no.10(October 19, 2012)
- ISSN：1554-8937
文摘
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尾), some of which inhibit channel activity. Cortisone potentiates Kv1 channel by binding to Kv尾 and promoting its dissociation from the channel, but its half-maximum effective concentration is 46 渭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 卤 1.1 nM. Further studies showed that fluticasone propionate potentiates channel current by inducing dissociation of Kv尾, and docking of fluticasone propionate into the cortisone binding 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尾 complex.