Norfluoxetine inhibits TREK-2 K2P channels by multiple mechanisms including state-independent effects on the selectivity filter gate.
Norfluoxetine inhibits TREK-2 K2P channels by multiple mechanisms including state-independent effects on the selectivity filter gate.
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DOI：
10.1085/jgp.202012812
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发表时间：
2021-08-02
期刊：
影响因子：
--
通讯作者：
Tucker SJ
中科院分区：
文献类型：
--
作者：
Proks P;Schewe M;Conrad LJ;Rao S;Rathje K;Rödström KEJ;Carpenter EP;Baukrowitz T;Tucker SJ
Proks等人表明，抗抑郁药去甲氟西汀通过调节TREK-2双孔结构域K+通道的开放和闭合状态之间的平衡以及其过滤器门控来影响TREK-2双孔结构域K+通道的行为。TREK亚家族的双孔结构域K+（K2 P）通道被氟西汀及其代谢产物去甲氟西汀（NFx）抑制。虽然不是这种抗抑郁药的主要靶点，但NFx对TREK通道的抑制为与通道门控相关的构象变化提供了重要见解，并突出了选择性过滤器在此过程中的作用。然而，尽管具有NFx结合的TREK-2晶体结构的可用性，但NFx抑制的精确机制仍然难以捉摸。NFx以前被认为是一种状态依赖性抑制剂，但其结合位点表明这种带正电荷的药物可能抑制通道活性的许多可能方式。在这里，我们表明，NFx施加多种影响单通道的行为，影响通道的开放和关闭状态，通道可以成为高度激活的2-APB，同时保持在向下的构象。我们还表明，NFx的抑制作用是无关的，其正电荷，但可以影响的激动剂，改变过滤器的稳定性，如ML 335，以及由一个内在的电压依赖性门控过程中的过滤器。因此，NFx不仅通过改变上下构象之间的平衡来抑制通道活性，而且还可以直接影响滤波器门控。这些结果提供了对调节TREK K2 P通道中的滤波器门控的复杂变构机制的进一步了解，并突出了可以调节滤波器门控以允许多模式调节的不同方式。
Proks et al. show that the antidepressant norfluoxetine affects the behavior of TREK-2 two-pore domain K+ channels by regulating the equilibrium between their open and closed states as well as their filter gating. The TREK subfamily of two-pore domain K+ (K2P) channels are inhibited by fluoxetine and its metabolite, norfluoxetine (NFx). Although not the principal targets of this antidepressant, TREK channel inhibition by NFx has provided important insights into the conformational changes associated with channel gating and highlighted the role of the selectivity filter in this process. However, despite the availability of TREK-2 crystal structures with NFx bound, the precise mechanisms underlying NFx inhibition remain elusive. NFx has previously been proposed to be a state-dependent inhibitor, but its binding site suggests many possible ways in which this positively charged drug might inhibit channel activity. Here we show that NFx exerts multiple effects on single-channel behavior that influence both the open and closed states of the channel and that the channel can become highly activated by 2-APB while remaining in the down conformation. We also show that the inhibitory effects of NFx are unrelated to its positive charge but can be influenced by agonists which alter filter stability, such as ML335, as well as by an intrinsic voltage-dependent gating process within the filter. NFx therefore not only inhibits channel activity by altering the equilibrium between up and down conformations but also can directly influence filter gating. These results provide further insight into the complex allosteric mechanisms that modulate filter gating in TREK K2P channels and highlight the different ways in which filter gating can be regulated to permit polymodal regulation.
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影响因子：
64.8
作者：
Li B;Rietmeijer RA;Brohawn SG
通讯作者：
Brohawn SG
影响因子：
56.9
作者：
Miller, Alexandria N.;Long, Stephen B.
通讯作者：
Long, Stephen B.
k（2p）2.1（Trek-1） - 激活器复合物揭示了一个隐秘的选择性滤波器结合位点。
影响因子：
64.8
作者：
Lolicato M;Arrigoni C;Mori T;Sekioka Y;Bryant C;Clark KA;Minor DL Jr
通讯作者：
Minor DL Jr
DOI：
10.1016/j.str.2017.03.006
发表时间：
2017-05-02
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Aryal P;Jarerattanachat V;Clausen MV;Schewe M;McClenaghan C;Argent L;Conrad LJ;Dong YY;Pike ACW;Carpenter EP;Baukrowitz T;Sansom MSP;Tucker SJ
通讯作者：
Tucker SJ
DOI：
10.1085/jgp.58.4.413
发表时间：
1971-10
期刊：
The Journal of general physiology
影响因子：
--
作者：
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通讯作者：
Armstrong CM