Zafar Sadia, Jabeen Ishrat
Research Center for Modeling and Simulation, National University of Sciences and Technology, Islamabad, Pakistan.
Front Chem. 2018 Sep 11;6:397. doi: 10.3389/fchem.2018.00397. eCollection 2018.
γ-Aminobutyric acid (GABA) Transporters (GATs) belong to sodium and chloride dependent-transporter family and are widely expressed throughout the brain. Notably, GAT1 is accountable for sustaining 75% of the synaptic GABA concentration and entails its transport to the GABA receptors to initiate the receptor-mediated inhibition of post-synaptic neurons. Imbalance in ion homeostasis has been associated with several neurological disorders related to the GABAergic system. However, inhibition of the GABA uptake by these transporters has been accepted as an effective approach to enhance GABAergic inhibitory neurotransmission in the treatment of seizures in epileptic and other neurological disorders. Here, we reviewed computational methodologies including molecular modeling, docking, and molecular dynamic simulations studies to underscore the structure and function of GAT1 in the GABAergic system. Additionally, various SAR and QSAR methodologies have been reviewed to probe the 3D structural features of inhibitors required to modulate GATs activity. Overall, present review provides an overview of crucial role of GAT1 in GABAergic system and its modulation to evade neurological disorders.
γ-氨基丁酸（GABA）转运体（GATs）属于钠和氯依赖性转运体家族，在整个大脑中广泛表达。值得注意的是，GAT1负责维持75%的突触GABA浓度，并将其转运至GABA受体，以启动受体介导的对突触后神经元的抑制作用。离子稳态失衡与多种与GABA能系统相关的神经疾病有关。然而，抑制这些转运体对GABA的摄取已被认为是在治疗癫痫和其他神经疾病中的癫痫发作时增强GABA能抑制性神经传递的有效方法。在此，我们综述了包括分子建模、对接和分子动力学模拟研究在内的计算方法，以强调GAT1在GABA能系统中的结构和功能。此外，还综述了各种构效关系（SAR）和定量构效关系（QSAR）方法，以探究调节GATs活性所需抑制剂的三维结构特征。总体而言，本综述概述了GAT1在GABA能系统中的关键作用及其调节以避免神经疾病。
