Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
Neuropharmacology. 2019 Dec 15;161:107548. doi: 10.1016/j.neuropharm.2019.02.030. Epub 2019 Feb 23.
The serotonin transporter (SERT) belongs to the monoamine transporter family, which also includes the dopamine and norepinephrine transporters. SERT is essential for regulating serotonergic signaling by the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron. Dysregulation of SERT has been implicated in several major psychiatric disorders such as major depressive disorder (MDD). MDD was among the top five leading causes of years lived with disease in 2016 and is characterized as a major global burden. Several drugs have been developed to target SERT for use in the treatment of MDD, and their respective binding modes and locations within SERT have been studied. The elucidation of the first structure of a bacterial SERT homologue in 2005 has accelerated crystallographic, computational, and functional studies to further elucidate drug binding and method of action in SERT. Herein, we aim to highlight and compare these studies with an emphasis on what the different experimental methods conclude on substrate and inhibitor binding modes, and the potential caveats of using the different types of studies are discussed. We focus this review on the binding of cognate substrate and drugs belonging to the different families of antidepressants, including tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and multimodal drugs, as well as illicit drugs such as cocaine, amphetamines, and ibogaine. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
血清素转运体（SERT）属于单胺转运体家族，该家族还包括多巴胺和去甲肾上腺素转运体。SERT 通过将血清素从突触间隙重新摄取回突触前神经元来调节血清素能信号。SERT 的失调与几种主要的精神疾病有关，如重度抑郁症（MDD）。MDD 是 2016 年导致患病年数最多的前 5 大疾病之一，是一个主要的全球性负担。已经开发了几种针对 SERT 的药物来治疗 MDD，并且已经研究了它们在 SERT 中的各自结合模式和位置。2005 年第一个细菌 SERT 同源物结构的阐明加速了晶体学、计算和功能研究，以进一步阐明 SERT 中的药物结合和作用方式。在此，我们旨在强调和比较这些研究，重点是不同的实验方法对底物和抑制剂结合模式的结论，以及使用不同类型的研究的潜在局限性。我们将本综述的重点放在与同源底物和属于不同类别的抗抑郁药（包括三环类抗抑郁药、选择性 5-羟色胺再摄取抑制剂、5-羟色胺-去甲肾上腺素再摄取抑制剂和多模式药物）以及非法药物（如可卡因、安非他命和伊博加因）的结合上。本文是题为“神经递质转运体特刊”的一部分。
