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Molecular Cell:神经递质转运机制的新发现

来源:科学网 2008-07-18 11:07

(封面图片:与钠离子相关的LeuT协同转运机制示意图。)

真核生物神经递质(eukaryotic neurotransmitter)钠转运体(NSSs)是一种能终止神经传递过程的物质,其作用机理主要是通过钠驱动的再吸收,因此钠转运体是多种抗抑郁剂以及中枢神经兴奋剂作用的目标。而在原核生物中,存在一种类似功能的NSS物质—LeuT,LeuT是依赖于钠离子的神经转运蛋白在细菌等中的一种同源结构,其晶体结构表现出一种一个亮氨酸及两个钠离子结合在一起的闭合状态,但是该物质的晶体结构却无法全面揭示转运的分子学机制。

在2008年6月20日出版的《分子细胞》(Molecular Cell)上,来自美国的一组科学家发表文章称,他们找到了依赖于钠离子的底物转运循环。通过一种称为“拉伸分子动力学模拟”(steered molecular dynamics simulation)的技术,研究小组找到了LeuT的底物转运途径。在计算模拟过程中,科研人员发现存在一个次级底物结合位点,该位点位于胞外前庭(extracellular vestibule),并且其包含的残留物显示最近发生过与三环抗抑郁剂(tricyclic antidepressants)的结合。

进一步实验显示,两个结合位点能同时被占据,次级位点的底物可变构触发细胞内钠离子以及初级位点底物的释放,因此其作用相当于“协同转运效应子”。由于三环抗抑郁剂能结合于该次级位点,初级位点的底物释放不会被促进,也就是说,抗抑郁类药物和中枢神经兴奋剂等能和结合底物产生竞争,而与底物不同的是,当这些抗抑郁剂和兴奋剂结合到位点上之后,并不能像底物一样触发释放,因此抗抑郁剂可作为协同转运解偶联剂,并起到抑制转运的作用。(生物谷Bioon.com)

生物谷推荐原始出处:

Molecular Cell,Vol 30, 667-677, 20 June 2008,Lei Shi, Jonathan A. Javitch

The Mechanism of a Neurotransmitter:Sodium Symporter—Inward Release of Na+ and Substrate Is Triggered by Substrate in a Second Binding Site

Lei Shi,1,2,7 Matthias Quick,3,6,7 Yongfang Zhao,3 Harel Weinstein,1,2 and Jonathan A. Javitch3,4,5,6,

1 Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA
2 HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA
3 Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
4 Department of Psychiatry, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
5 Department of Pharmacology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
6 Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA

Summary


Eukaryotic neurotransmitter:sodium symporters (NSSs), targets for antidepressants and psychostimulants, terminate neurotransmission by sodium-driven reuptake. The crystal structure of LeuTAa, a prokaryotic NSS homolog, revealed an occluded state in which one leucine and two Na+ ions are bound, but provided limited clues to the molecular mechanism of transport. Using steered molecular dynamics simulations, we explored the substrate translocation pathway of LeuT. We identified a second substrate binding site located in the extracellular vestibule comprised of residues shown recently to participate in binding tricyclic antidepressants. Binding and flux experiments showed that the two binding sites can be occupied simultaneously. The substrate in the secondary site allosterically triggers intracellular release of Na+ and substrate from the primary site, thereby functioning as a “symport effector.” Because tricyclic antidepressants bind differently to this secondary site, they do not promote substrate release from the primary site and thus act as symport uncouplers and inhibit transport.

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