A novel small-molecule selective activator of homomeric GIRK4 channels.
A novel small-molecule selective activator of homomeric GIRK4 channels.
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DOI：
10.1016/j.jbc.2022.102009
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发表时间：
2022-06
影响因子：
4.8
通讯作者：
Logothetis, Diomedes E.
中科院分区：
文献类型：
--
作者：
Cui, Meng;Xu, Keman;Gada, Kirin D.;Shalomov, Boris;Ban, Michelle;Eptaminitaki, Giasemi C.;Kawano, Takeharu;Plant, Leigh D.;Dascal, Nathan;Logothetis, Diomedes E.
G蛋白敏感性内向整流钾通道（GIRK）是神经、心脏和内分泌疾病的重要药物靶点。尽管近年来已经发现了许多GIRK通道调节剂，但大多数缺乏选择性。GIRK通道作为同聚体（即，GIRK 2和GIRK 4）或异聚体（例如，GIRK 1/2、GIRK 1/4和GIRK 2/3）四聚体。激活剂，如ML 297，伊维菌素，和GAT 1508，已被证明激活异聚体GIRK 1/2通道比GIRK 1/4通道更好，具有不同程度的选择性，但不是同源GIRK 2和GIRK 4通道。此外，VU 0529331被发现为第一个同源GIRK通道激活剂，但它对GIRK 2的选择性弱于GIRK 4（或G4）同源通道。在这里，我们报告了第一个高选择性的小分子激活剂靶向GIRK 4同源通道，3 hi 2 one-G4（3-[2-（3，4-二甲氧基苯基）-2-氧代乙基]-3-羟基-1-（1-萘基甲基）-1，3-二氢-2H-吲哚-2-酮）。我们发现3 hi 2 one-G4不激活GIRK 2、GIRK 1/2或GIRK 1/4通道。使用分子建模，诱变，和电生理学，我们分析了3 hi 2 one-G4的结合位点形成的跨膜1，跨膜2，和滑动螺旋区的GIRK 4通道，磷脂酰肌醇-4，5-二磷酸结合位点附近，并表明，它会导致通道激活通过加强通道-磷脂酰肌醇-4，5-二磷酸相互作用。我们还确定幻灯片螺旋残基L77 GIRK 4，对应于残基I82 GIRK 2，作为一个主要的决定因素的亚型特异性的选择性。我们提出3 hi 2 one-G4可以作为研究GIRK 4通道功能的有用的药物探针，也可以在药物优化研究中进行，以解决GIRK 4相关疾病，如原发性醛固酮增多症和迟发性肥胖症。
G protein–sensitive inwardly rectifying potassium (GIRK) channels are important pharmaceutical targets for neuronal, cardiac, and endocrine diseases. Although a number of GIRK channel modulators have been discovered in recent years, most lack selectivity. GIRK channels function as either homomeric (i.e., GIRK2 and GIRK4) or heteromeric (e.g., GIRK1/2, GIRK1/4, and GIRK2/3) tetramers. Activators, such as ML297, ivermectin, and GAT1508, have been shown to activate heteromeric GIRK1/2 channels better than GIRK1/4 channels with varying degrees of selectivity but not homomeric GIRK2 and GIRK4 channels. In addition, VU0529331 was discovered as the first homomeric GIRK channel activator, but it shows weak selectivity for GIRK2 over GIRK4 (or G4) homomeric channels. Here, we report the first highly selective small-molecule activator targeting GIRK4 homomeric channels, 3hi2one-G4 (3-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-3-hydroxy-1-(1-naphthylmethyl)-1,3-dihydro-2H-indol-2-one). We show that 3hi2one-G4 does not activate GIRK2, GIRK1/2, or GIRK1/4 channels. Using molecular modeling, mutagenesis, and electrophysiology, we analyzed the binding site of 3hi2one-G4 formed by the transmembrane 1, transmembrane 2, and slide helix regions of the GIRK4 channel, near the phosphatidylinositol-4,5-bisphosphate binding site, and show that it causes channel activation by strengthening channel–phosphatidylinositol-4,5-bisphosphate interactions. We also identify slide helix residue L77 in GIRK4, corresponding to residue I82 in GIRK2, as a major determinant of isoform-specific selectivity. We propose that 3hi2one-G4 could serve as a useful pharmaceutical probe in studying GIRK4 channel function and may also be pursued in drug optimization studies to tackle GIRK4-related diseases such as primary aldosteronism and late-onset obesity.
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DOI：
10.1073/pnas.0803261105
发表时间：
2008-06-10
影响因子：
11.1
作者：
Perry, Cydne A.;Pravetoni, Marco;Wickman, Kevin
通讯作者：
Wickman, Kevin
DOI：
10.1126/science.1198785
发表时间：
2011-02-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Choi M;Scholl UI;Yue P;Björklund P;Zhao B;Nelson-Williams C;Ji W;Cho Y;Patel A;Men CJ;Lolis E;Wisgerhof MV;Geller DS;Mane S;Hellman P;Westin G;Åkerström G;Wang W;Carling T;Lifton RP
通讯作者：
Lifton RP
DOI：
10.1073/pnas.1211305109
发表时间：
2012-08-28
影响因子：
11.1
作者：
Idevall-Hagren, Olof;Dickson, Eamonn J.;De Camilli, Pietro
通讯作者：
De Camilli, Pietro
影响因子：
5.5
作者：
Ho, IHM;Murrell-Lagnado, RD
通讯作者：
Murrell-Lagnado, RD
影响因子：
5
作者：
Kaufmann, Kristian;Romaine, Ian;Weaver, C. David
通讯作者：
Weaver, C. David