真核生物神經遞質（eukaryotic neurotransmitter）鈉轉運體（NSSs）是一種能終止神經傳遞過程的物質，其作用機理主要是通過鈉驅動的再吸收,，因此鈉轉運體是多種抗抑郁劑以及中樞神經興奮劑作用的目標,。而在原核生物中，存在一種類似功能的NSS物質—LeuT,，LeuT是依賴于鈉離子的神經轉運蛋白在細菌等中的一種同源結構,，其晶體結構表現出一種一個亮氨酸及兩個鈉離子結合在一起的閉合狀態(tài)，但是該物質的晶體結構卻無法全面揭示轉運的分子學機制,。
在2008年6月20日出版的《分子細胞》（Molecular Cell）上，來自美國的一組科學家發(fā)表文章稱,，他們找到了依賴于鈉離子的底物轉運循環(huán),。通過一種稱為“拉伸分子動力學模擬”（steered molecular dynamics simulation）的技術，研究小組找到了LeuT的底物轉運途徑,。在計算模擬過程中,，科研人員發(fā)現存在一個次級底物結合位點，該位點位于胞外前庭（extracellular vestibule）,，并且其包含的殘留物顯示最近發(fā)生過與三環(huán)抗抑郁劑（tricyclic antidepressants）的結合,。
進一步實驗顯示，兩個結合位點能同時被占據,，次級位點的底物可變構觸發(fā)細胞內鈉離子以及初級位點底物的釋放,，因此其作用相當于“協同轉運效應子”。由于三環(huán)抗抑郁劑能結合于該次級位點,，初級位點的底物釋放不會被促進,，也就是說，抗抑郁類藥物和中樞神經興奮劑等能和結合底物產生競爭,，而與底物不同的是，當這些抗抑郁劑和興奮劑結合到位點上之后,，并不能像底物一樣觸發(fā)釋放,，因此抗抑郁劑可作為協同轉運解偶聯劑，并起到抑制轉運的作用,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
