孕激素激活含有β1的BK通道涉及两个结合位点
Kelsey C North1, Andrew A Shaw1, Anna N Bukiya1
1Department of Pharmacology, Addiction Science, and Toxicology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38103, USA.
Nature communications
|November 9, 2023
概括
孕激素激活大脑血管BK通道,帮助从脑缺血中恢复. 这一行动涉及BK通道监管子单元的特定结合点,提供新的治疗点.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 孕激素 (≥1μM) 有助于大脑缺血的恢复,可能通过大脑血管扩张.
- 孕激素对脑血管的影响的特定分子标仍然未确定.
- 大脑血管光滑肌细胞表达大导电激活 (BK) 通道.
研究的目的:
- 在脑血管肌细胞中识别孕激素作用的分子标.
- 阐明孕激素激活BK通道的机制.
- 研究BK通道调节子单元在孕激素介导的大脑血管效应中的作用.
主要方法:
- 电生理学记录 (例如,鼠标脑血管肌细胞和异质表达系统的补丁)
- BK通道α和β1/β4调控子单元的位点定向突变发生.
- 在体内和体外研究评估大脑血管对孕激素和酒精的反应.
主要成果:
- 微分子孕激素激活小鼠脑血管肌细胞中的BK通道,依赖于β1和β4亚单元.
- 孕激素结合于β1/β4亚单元上的保守的类固醇结合点,具有明显的高亲和和低亲和位点.
- 在β1亚单元的关键残留物 (Trp87,Tyr32,Trp163) 中的突变消除了孕激素诱导的通道激活和脑血管扩张.
结论:
- 孕激素通过一种机制激活大脑血管BK通道,该机制涉及β1/β4调节子单元上的高和低亲和度结合点.
- 这种激活对于孕激素介导的大脑血管扩张和脑缺血的恢复至关重要.
- 孕激素对抗酒精诱导的大脑血管收缩,表明治疗潜力.
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