The inhibitory neurotransmitter γ-aminobutyric acid (GABA) is cleared from the synaptic cleft by the sodium- and chloride-coupled GABA transporter GAT1. Inhibition of GAT1 prolongs the GABAergic signaling at the synapse and is a strategy to treat certain forms of epilepsy. In this study, we present the cryo-electron microscopy structure of Rattus norvegicus GABA transporter 1 (rGAT1) at a resolution of 3.1 Å. The structure elucidation was facilitated by epitope transfer of a fragment-antigen binding (Fab) interaction site from the Drosophila dopamine transporter (dDAT) to rGAT1. The structure reveals rGAT1 in a cytosol-facing conformation, with a linear density in the primary binding site that accommodates a molecule of GABA, a displaced ion density proximal to Na site 1 and a bound chloride ion. A unique insertion in TM10 aids the formation of a compact, closed extracellular gate. Besides yielding mechanistic insights into ion and substrate recognition, our study will enable the rational design of specific antiepileptics.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10352132 | PMC |
| http://dx.doi.org/10.1038/s41594-023-01011-w | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Functional omics of ORP7 in primary endothelial cells.
BMC Biol
December 2024
Minerva Foundation Institute for Medical Research, Tukholmankatu 8, 00290, Helsinki, Finland.
Background: Many members of the oxysterol-binding protein-related protein (ORP) family have been characterized in detail over the past decades, but the lipid transport and other functions of ORP7 still remain elusive. What is known about ORP7 points toward an endoplasmic reticulum and plasma membrane-localized protein, which also interacts with GABA type A receptor-associated protein like 2 (GABARAPL2) and unlipidated Microtubule-associated proteins 1A/1B light chain 3B (LC3B), suggesting a further autophagosomal/lysosomal association. Functional roles of ORP7 have been suggested in cholesterol efflux, hypercholesterolemia, and macroautophagy.
View Article and Find Full Text PDFImpairment of Skeletal Muscle Contraction by Inhibitors of GABA Transporters.
Int J Mol Sci
November 2024
Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, P.O. Box 30, Kazan 420111, Russia.
γ-Aminobutyric acid (GABA) has a significant impact on the functioning of not only the central but also the peripheral part of the nervous system. Recently, various elements of the GABAergic signaling system have been discovered in the area of the neuromuscular junction of mammals. At the same time, the functional activity of membrane-bound GABA transporters (GATs) and their role in neuromuscular transmission have not been identified.
View Article and Find Full Text PDFEndogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
Autophagy
December 2024
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, Barcelona, Spain.
MFN1 (mitofusin 1) and MFN2 are key players in mitochondrial fusion, endoplasmic reticulum (ER)-mitochondria juxtaposition, and macroautophagy/autophagy. However, the mechanisms by which these proteins participate in these processes are poorly understood. Here, we studied the interactomes of these two proteins by using CRISPR-Cas9 technology to insert an HA-tag at the C terminus of MFN1 and MFN2, and thus generating HeLa cell lines that endogenously expressed MFN1-HA or MFN2-HA.
View Article and Find Full Text PDFPost mortem validation and mechanistic study of UCB-J in progressive supranuclear palsy patients' brains.
Alzheimers Dement
December 2024
Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Introduction: Progressive supranuclear palsy (PSP) is a devastating 4R tauopathy affecting motor functions and is often misdiagnosed/underdiagnosed due to a lack of specific biomarkers. Synaptic loss is an eminent feature of tauopathies including PSP. Novel synaptic positron emission tomography tracer UCB-J holds great potential for early diagnosis; however, there is a substantial knowledge gap in terms of the mechanism and the extent and nature of synaptic loss in PSP.
View Article and Find Full Text PDFRole of BDNF-TrkB signaling in the improvement of motor function and neuroplasticity after ischemic stroke in rats by transcranial direct current stimulation.
Brain Res Bull
December 2024
Department of Rehabilitation, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address:
Background: Transcranial direct current stimulation (tDCS) has an impact on improving cognitive and motor dysfunction induced by ischemia-reperfusion injury. However, to use this technology more rationally in clinical practice, a deepened understanding of the molecular mechanisms behind its therapeutic effects is needed. This study explored the role of the brain-derived neurotrophic factor(BDNF) and its associated receptor tropomyosin-receptor kinase B(TrkB) while deciphering the underlying mechanisms in transcranial direct current therapy to treat ischemic stroke.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!