Structure, Function, and Modulation of γ-Aminobutyric Acid Transporter 1 (GAT1) in Neurological Disorders: A Pharmacoinformatic Prospective

Abstract

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 GABAA 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.

Modeling and Simulation of hGAT1: A Mechanistic Investigation of the GABA Transport Process

“…In di-sodium h GAT1 complex ( hGAT 1 out N 1+2 ), both Na1 and Na2 ions were observed at a interatomic distance of 7.6 Å. Both sodium binding sites are separated and screened from one another by residues A61 and I62, each of which forms a direct interaction with one of the sodium ions [ 46 , 47 ]. The addition of GABA to the di-sodium complex ( hGAT 1 out G , N 1+2 ) resulted in an increase in the interatomic distances between Na1 with S295 to 5.6 Å and N327 to 5.1 Å while the interactions between Na1 and A61, N66, S295 were relatively preserved.…”

A Reappraisal of GAT-1 Localization in Neocortex

“…As the major GABA transporter in the brain, it plays a key role in modulating GABA signaling (Cherubini and Conti, 2001;Scimemi, 2014). Besides being involved in a broad range of brain functions (Cherubini and Conti, 2001;Bragina et al, 2008;Conti et al, 2011;Kinjo et al, 2013;Scimemi, 2014;Savtchenko et al, 2015;Zafar and Jabeen, 2018), GAT-1 has also been implicated in the pathophysiology of a number of neuropsychiatric disorders including anxiety, depression, epilepsy, Alzheimer's disease, and schizophrenia (Lai et al, 1998;Nägga et al, 1999;Pierri et al, 1999;Sundman-Eriksson and Allard, 2002;Conti et al, 2004;Lewis and Gonzalez-Burgos, 2006;Cope et al, 2009;Bitanihirwe and Woo, 2014;Carvill et al, 2015;Gong et al, 2015;Fuhrer et al, 2017;Mattison et al, 2018).…”

Mild phenotype associated with SLC6A1 gene mutation: A case report with literature review

“…GAT-1 has a critical role for the GABA reuptake from the synapses. [2] The clinical picture of SLC6A1 gene mutations is characterized by a broader spectrum including a mild-to-moderate intellectual disability, speech difficulties, behavioral problems (such as hyperactivity, attention deficit, aggressiveness, and autistic traits), epilepsy (often with myoclonic-atonic and atypical absence seizures, characterizing a myoclonic-atonic epilepsy), and neurological signs (ataxia or unsteady gait, hypotonia, tremor, and fine-motor impairment). [34]…”