Nepal Binod, Das Sanjay, Reith Maarten E, Kortagere Sandhya
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States.
Department of Psychiatry, New York University School of Medicine, New York City, NY, United States.
Front Physiol. 2023 Mar 3;14:1150355. doi: 10.3389/fphys.2023.1150355. eCollection 2023.
The dopamine transporter (DAT) plays an integral role in dopamine neurotransmission through the clearance of dopamine from the extracellular space. Dysregulation of DAT is central to the pathophysiology of numerous neuropsychiatric disorders and as such is an attractive therapeutic target. DAT belongs to the solute carrier family 6 (SLC6) class of Na/Cl dependent transporters that move various cargo into neurons against their concentration gradient. This review focuses on DAT (SCL6A3 protein) while extending the narrative to the closely related transporters for serotonin and norepinephrine where needed for comparison or functional relevance. Cloning and site-directed mutagenesis experiments provided early structural knowledge of DAT but our contemporary understanding was achieved through a combination of crystallization of the related bacterial transporter LeuT, homology modeling, and subsequently the crystallization of DAT. These seminal findings enabled a better understanding of the conformational states involved in the transport of substrate, subsequently aiding state-specific drug design. Post-translational modifications to DAT such as phosphorylation, palmitoylation, ubiquitination also influence the plasma membrane localization and kinetics. Substrates and drugs can interact with multiple sites within DAT including the primary S1 and S2 sites involved in dopamine binding and novel allosteric sites. Major research has centered around the question what determines the substrate and inhibitor selectivity of DAT in comparison to serotonin and norepinephrine transporters. DAT has been implicated in many neurological disorders and may play a role in the pathology of HIV and Parkinson's disease direct physical interaction with HIV-1 Tat and α-synuclein proteins respectively.
多巴胺转运体（DAT）通过清除细胞外空间中的多巴胺，在多巴胺神经传递中发挥着不可或缺的作用。DAT功能失调是众多神经精神疾病病理生理学的核心，因此是一个有吸引力的治疗靶点。DAT属于溶质载体家族6（SLC6）类的Na/Cl依赖性转运体，可逆浓度梯度将各种物质转运到神经元中。本综述聚焦于DAT（SCL6A3蛋白），同时在需要进行比较或探讨功能相关性时，将叙述扩展至与血清素和去甲肾上腺素密切相关的转运体。克隆和定点诱变实验提供了DAT的早期结构知识，但我们目前的理解是通过相关细菌转运体LeuT的结晶、同源建模以及随后DAT的结晶相结合而实现的。这些开创性的发现使我们能够更好地理解底物转运过程中涉及的构象状态，进而有助于进行针对特定状态的药物设计。DAT的翻译后修饰，如磷酸化、棕榈酰化、泛素化，也会影响其质膜定位和动力学。底物和药物可与DAT内的多个位点相互作用，包括参与多巴胺结合的主要S1和S2位点以及新的变构位点。主要研究集中在与血清素和去甲肾上腺素转运体相比，是什么决定了DAT对底物和抑制剂的选择性这一问题上。DAT与许多神经系统疾病有关，可能分别通过与HIV-1 Tat和α-突触核蛋白的直接物理相互作用，在HIV和帕金森病的病理过程中发挥作用。
