State-dependent inhibition of BK channels by the opioid agonist loperamide.
State-dependent inhibition of BK channels by the opioid agonist loperamide.
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DOI：
10.1085/jgp.202012834
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发表时间：
2021-09-06
期刊：
影响因子：
--
通讯作者：
Rothberg BS
中科院分区：
文献类型：
--
作者：
Vouga AG;Rockman ME;Yan J;Jacobson MA;Rothberg BS
Alfrega等人表明阿片受体激动剂洛哌丁胺是大电导Ca 2+激活的K+（BK）通道的抑制剂，可作为状态依赖性孔阻滞剂。洛哌丁胺可能部分通过抑制肠内钾外流发挥其治疗作用。大电导Ca 2+激活的K+（BK）通道控制着一系列生理功能，其功能障碍与人类疾病有关。我们发现，广泛应用的药物洛哌丁胺（LOP）可抑制由α亚基（BKα通道）或α亚基加辅助γ1亚基（BKα/γ1通道）组成的BK通道的活性，并对其作用的分子机制进行了分析。LOP施加在细胞溶质侧的膜迅速和可逆地抑制BK电流，电压激活的BK电流的衰减出现的效果。对LOP的表观亲和力随着超极化而降低，其方式与LOP作为开放激活通道的抑制剂的行为一致。增加LOP浓度降低了半最大激活电压，与LOP抑制开放状态的相对稳定一致。单通道记录显示，LOP并没有减少单一的BK通道电流，而是减少BK通道的开放概率和平均开放时间。LOP引起的使用依赖性抑制，其中列车的简短的去极化步骤导致BK电流的累积减少，而单一的简短的去极化步骤没有。LOP对BK通道门控的主要影响由LOP作为状态依赖性孔阻滞剂的机制描述。我们的研究结果表明，治疗剂量的LOP可能通过抑制K+流出通过肠道BK通道的一部分。
Vouga et al. show that the opioid receptor agonist loperamide is an inhibitor of large-conductance Ca2+-activated K+ (BK) channels that acts as a state-dependent pore blocker. Loperamide may exert its therapeutic effect partly by inhibiting potassium efflux in the intestine. Large-conductance Ca2+-activated K+ (BK) channels control a range of physiological functions, and their dysfunction is linked to human disease. We have found that the widely used drug loperamide (LOP) can inhibit activity of BK channels composed of either α-subunits (BKα channels) or α-subunits plus the auxiliary γ1-subunit (BKα/γ1 channels), and here we analyze the molecular mechanism of LOP action. LOP applied at the cytosolic side of the membrane rapidly and reversibly inhibited BK current, an effect that appeared as a decay in voltage-activated BK currents. The apparent affinity for LOP decreased with hyperpolarization in a manner consistent with LOP behaving as an inhibitor of open, activated channels. Increasing LOP concentration reduced the half-maximal activation voltage, consistent with relative stabilization of the LOP-inhibited open state. Single-channel recordings revealed that LOP did not reduce unitary BK channel current, but instead decreased BK channel open probability and mean open times. LOP elicited use-dependent inhibition, in which trains of brief depolarizing steps lead to accumulated reduction of BK current, whereas single brief depolarizing steps do not. The principal effects of LOP on BK channel gating are described by a mechanism in which LOP acts as a state-dependent pore blocker. Our results suggest that therapeutic doses of LOP may act in part by inhibiting K+ efflux through intestinal BK channels.
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DOI：
10.1085/jgp.109.5.647
发表时间：
1997-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Cui J;Cox DH;Aldrich RW
通讯作者：
Aldrich RW
DOI：
10.1085/jgp.200609521
发表时间：
2006-10
期刊：
The Journal of general physiology
影响因子：
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作者：
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通讯作者：
Aldrich RW
影响因子：
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作者：
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Shayanfar, Ali
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作者：
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影响因子：
4.6
作者：
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