Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition
Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition
复制标题
甘氨酸受体的托烷司琼调节：飞摩尔增强和抑制的分子决定因素
作者：
Zhe Yang;Agnieszka D Ney;B. Cromer;H. Ng;M. Parker;J. Lynch
5 -羟色胺3型受体拮抗剂托烷司琼作为抗吐药在临床使用。该化合物对甘氨酸受体氯离子通道具有增强和抑制作用。抑制作用发生在微摩尔浓度下，而增强作用则发生在飞摩尔浓度的同质α1受体上。只有当托司司琼在甘氨酸的存在下应用时才会发生增强作用。我们还试图通过位于已知配体结合位点或附近的序列突变残基来确定托咪司司酮抑制α1甘氨酸受体的分子决定因素。我们发现N102的保守突变消除了托烷司琼的抑制作用，而不影响托烷司琼增强的幅度或敏感性。包括托烷司琼、阿托品和SB203186的结构-活性分析在内的几条证据表明，N102可能通过H键与托烷司琼的tropane氮结合。β亚基N125残基（对应α1亚基N102）的突变对托替司琼抑制效力影响不大。这些结果表明N102是抑制托烷司琼而非增强托烷司琼所必需的，并且抑制性托烷司琼在不同的亚基界面上以不同的方向结合。据我们所知，托烷司琼是目前已知的对cys - loop受体最为敏感的调制剂。
The 5‐hydroxytryptamine type‐3 receptor antagonist tropisetron is in clinical use as an anti‐emetic drug. This compound also exerts both potentiating and inhibitory effects on the glycine receptor chloride channel. The inhibitory effects occur at micromolar concentrations, whereas the potentiating effects are shown here to occur at femtomolar concentrations at the homomeric α1 receptor. Potentiation occurred only when tropisetron was applied in the presence of glycine. We also sought to identify molecular determinants of tropisetron inhibition at the α1 glycine receptor by serially mutating residues located in or near known ligand‐binding sites. We discovered that conservative mutations to N102 ablated tropisetron inhibition without affecting the magnitude or sensitivity of tropisetron potentiation. Several lines of evidence, including a structure‐activity analysis of tropisetron, atropine and SB203186, suggest that N102 may bind to the tropisetron tropane nitrogen via H‐bonding. Mutation of the N125 residue in the β subunit, which corresponds to N102 in the α1 subunit, had little effect on tropisetron inhibitory potency. These results show that N102 is required for tropisetron inhibition but not potentiation and that inhibitory tropisetron binds in different orientations at different subunit interfaces. To our knowledge, tropisetron is the most exquisitely sensitive modulator yet identified for a cys‐loop receptor.
影响因子：
5.6
作者：
Unwin, N
通讯作者：
Unwin, N
胆碱酯酶与紧密结合抑制剂相互作用的分子基础。
DOI：
10.1016/j.cbi.2005.10.020
发表时间：
2005
期刊：
Chemico-biological interactions.
影响因子：
--
作者：
Radic,Zoran;Manetsch,Roman;Krasinski,Antoni;Raushel,Jessica;Yamauchi,John;Garcia,Cindy;Kolb,Hartmuth;Sharpless,KBarry;Taylor,Palmer
通讯作者：
Taylor,Palmer