• Guastella, J. et al. Cloning and expression of a rat brain GABA transporter. Science 249, 1303–1306 (1990).

    ADS 
    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Madsen, K. K., White, H. S. & Schousboe, A. Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol. Ther. 125, 394–401 (2010).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Braestrup, C. et al. (R)-N-[4,4-bis(3-methyl-2-thienyl)but-3-en-1-yl]nipecotic acid binds with high affinity to the brain gamma-aminobutyric acid uptake carrier. J. Neurochem. 54, 639–647 (1990).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Blat, Y. Non-competitive inhibition by active site binders. Chem. Biol. Drug Des. 75, 535–540 (2010).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Sieghart, W. Structure, pharmacology, and function of GABAA receptor rubtypes. GABA 54, 231–263 (2006).

    CAS 
    Article 

    Google Scholar
     

  • Bowery, N. G. et al. International Union of Pharmacology. XXXIII. Mammalian γ-aminobutyric acidB receptors: structure and function. Pharmacol. Rev. 54, 247–264 (2002).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Fattorini, G., Melone, M. & Conti, F. A reappraisal of GAT-1 localization in neocortex. Front. Cell. Neurosci. 14, 9 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Roberts, B. M. et al. GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model. Nat. Commun. 11, 4958 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Mermer, F. et al. Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons. Brain 144, 2499–2512 (2021).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Rosenthal, M. Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control. J. Clin. Psychiatry 64, 1245–1249 (2003).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Lyu, S. et al. Blockade of GABA transporter-1 and GABA transporter-3 in the lateral habenula improves depressive-like behaviors in a rat model of Parkinson’s disease. Neuropharmacology 181, 108369 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Fuhrer, T. E. et al. Impaired expression of GABA transporters in the human Alzheimer’s disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus. Neuroscience 351, 108–118 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Paparrigopoulos, T., Tzavellas, E., Karaiskos, D., Malitas, P. & Liappas, I. An open pilot study of tiagabine in alcohol dependence: tolerability and clinical effects. J. Psychopharmacol. 24, 1375–1380 (2010).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Schwartz, T. L. et al. An open-label study of tiagabine as augmentation therapy for anxiety. Ann. Clin. Psychiatry 17, 167–172 (2005).

    PubMed 
    Article 

    Google Scholar
     

  • Carpenter, L. L. et al. Open-label tiagabine monotherapy for major depressive disorder with anxiety. J. Clin. Psychiatry 67, 66–71 (2006).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Kragholm, B. et al. Discovery of a subtype selective inhibitor of the human betaine/GABA transporter 1 (BGT-1) with a non-competitive pharmacological profile. Biochem. Pharmacol. 86, 521–528 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Hauke, T. J., Wein, T., Höfner, G. & Wanner, K. T. Novel allosteric ligands of γ-aminobutyric acid transporter 1 (GAT1) by MS based screening of pseudostatic hydrazone libraries. J. Med. Chem. 61, 10310–10332 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Jurik, A. et al. A binding mode hypothesis of tiagabine confirms liothyronine effect on γ-aminobutyric acid transporter 1 (GAT1). J. Med. Chem. 58, 2149–2158 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Zafar, S. & Jabeen, I. Molecular dynamic simulations to probe stereoselectivity of tiagabine binding with human GAT1. Molecules 25, 4745 (2020).

    CAS 
    PubMed Central 
    Article 

    Google Scholar
     

  • Skovstrup, S., David, L., Taboureau, O. & Jørgensen, F. S. A steered molecular dynamics study of binding and translocation processes in the GABA transporter. PLoS ONE 7, e39360 (2012).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Keynan, S., Suh, Y. J., Kanner, B. I. & Rudnick, G. Expression of a cloned gamma-aminobutyric acid transporter in mammalian cells. Biochemistry 31, 1974–1979 (1992).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Cammack, J. N., Rakhilin, S. V. & Schwartz, E. A. A GABA transporter operates asymmetrically and with variable stoichiometry. Neuron 13, 949–960 (1994).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Lester, H. A., Mager, S., Quick, M. W. & Corey, J. L. Permeation properties of neurotransmitter transporters. Annu. Rev. Pharmacol. Toxicol. 34, 219–249 (1994).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Jardetzky, O. Simple allosteric model for membrane pumps. Nature 211, 969–970 (1966).

    ADS 
    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Krishnamurthy, H. & Gouaux, E. X-ray structures of LeuT in substrate-free outward-open and apo inward-open states. Nature 481, 469–474 (2012).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Penmatsa, A., Wang, K. H. & Gouaux, E. X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature 503, 85–90 (2013).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Gotfryd, K. et al. X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release. Nat. Commun. 11, 1005 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Singh, S. K., Yamashita, A. & Gouaux, E. Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448, 952–956 (2007).

    ADS 
    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Coleman, J. A., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–339 (2016).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Coleman, J. A. et al. Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport. Nature 569, 141–145 (2019).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Shahsavar, A. et al. Structural insights into the inhibition of glycine reuptake. Nature 591, 677–681 (2021).

    ADS 
    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Zhou, Z. et al. LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317, 1390–1393 (2007).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Kantcheva, A. K. et al. Chloride binding site of neurotransmitter sodium symporters. Proc. Natl Acad. Sci. USA 110, 8489–8494 (2013).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Li, F. et al. Ion transport and regulation in a synaptic vesicle glutamate transporter. Science 368, 893–897 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Zimmermann, I. et al. Synthetic single domain antibodies for the conformational trapping of membrane proteins. eLife 7, e34317 (2018).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Tsutsumi, N. et al. Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling. eLife 9, e58464 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Wu, X. & Rapoport, T. A. Cryo-EM structure determination of small proteins by nanobody-binding scaffolds (Legobodies). Proc. Natl Acad. Sci. USA 118, e2115001118 (2021).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Borden, L. A. et al. Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1. Eur. J. Pharmacol. 269, 219–224 (1994).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Suzdak, P. D., Foged, C. & Andersen, K. E. Quantitative autoradiographic characterization of the binding of [3H]tiagabine (NNC 05-328) to the GABA uptake carrier. Brain Res. 647, 231–241 (1994).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Korkhov, V. M., Farhan, H., Freissmuth, M. & Sitte, H. H. Oligomerization of the γ-aminobutyric acid transporter-1 is driven by an interplay of polar and hydrophobic interactions in transmembrane helix II. J. Biol. Chem. 279, 55728–55736 (2004).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • White, H. S. et al. Correlation between anticonvulsant activity and inhibitory action on glial gamma-aminobutyric acid uptake of the highly selective mouse gamma-aminobutyric acid transporter 1 inhibitor 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole and its N-alkylated analogs. J. Pharmacol. Exp. Ther. 302, 636–644 (2002).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Malinauskaite, L. et al. A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters. Nat. Struct. Mol. Biol. 21, 1006–1012 (2014).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Ben-Yona, A. & Kanner, B. I. Functional defects in the external and internal thin gates of the γ-aminobutyric acid (GABA) transporter GAT-1 can compensate each other. J. Biol. Chem. 288, 4549–4556 (2013).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Bismuth, Y., Kavanaugh, M. P. & Kanner, B. I. Tyrosine 140 of the gamma-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition. J. Biol. Chem. 272, 16096–16102 (1997).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Dhar, T. G. et al. Design, synthesis and evaluation of substituted triarylnipecotic acid derivatives as GABA uptake inhibitors: identification of a ligand with moderate affinity and selectivity for the cloned human GABA transporter GAT-3. J. Med. Chem. 37, 2334–2342 (1994).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Kanner, B. I. Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes. J. Biol. Chem. 278, 3705–3712 (2003).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Rudnick, G. Forty four years with Baruch Kanner and the chloride ion. Neurochem. Res. 47, 3–8 (2022).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Wang, K. H., Penmatsa, A. & Gouaux, E. Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature 521, 322–327 (2015).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Bulling, S. et al. The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. J. Biol. Chem. 287, 18524–18534 (2012).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Alberati, D. et al. Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology 62, 1152–1161 (2012).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Wang, X., Ratnaraj, N. & Patsalos, P. N. The pharmacokinetic inter-relationship of tiagabine in blood, cerebrospinal fluid and brain extracellular fluid (frontal cortex and hippocampus). Seizure 13, 574–581 (2004).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Sandtner, W. et al. Binding mode selection determines the action of ecstasy homologs at monoamine transporters. Mol. Pharmacol. 89, 165–175 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Clausen, R. P. et al. Structure–activity relationship and pharmacology of gamma-aminobutyric acid (GABA) transport inhibitors. Adv. Pharmacol. 54, 265–284 (2006).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Reith, M. E. A. et al. Novel C-1 substituted cocaine analogs unlike cocaine or benztropine. J. Pharmacol. Exp. Ther. 343, 413–425 (2012).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Alexandrov, A. I., Mileni, M., Chien, E. Y. T., Hanson, M. A. & Stevens, R. C. Microscale fluorescent thermal stability assay for membrane proteins. Structure 16, 351–359 (2008).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Punjani, A., Zhang, H. & Fleet, D. J. Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction. Nat. Methods 17, 1214–1221 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Bordoli, L. et al. Protein structure homology modeling using SWISS-MODEL workspace. Nat. Protoc. 4, 1–13 (2009).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Goddard, T. D., Huang, C. C. & Ferrin, T. E. Visualizing density maps with UCSF Chimera. J. Struct. Biol. 157, 281–287 (2007).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D60, 2126–2132 (2004).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Afonine, P. V. et al. Real-space refinement in PHENIX for cryo-EM and crystallography. Acta Crystallogr. D 74, 531–544 (2018).

    CAS 
    Article 

    Google Scholar
     

  • Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Abraham, M. J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 12, 19–25 (2015).

    ADS 
    Article 

    Google Scholar
     

  • Jo, S., Kim, T., Iyer, V. G. & Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 29, 1859–1865 (2008).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Kim, S. et al. CHARMM-GUI ligand reader and modeler for CHARMM force field generation of small molecules. J. Comput. Chem. 38, 1879–1886 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Leonard, A. N. & Lyman, E. Activation of G-protein-coupled receptors is thermodynamically linked to lipid solvation. Biophys. J. 120, 1777–1787 (2021).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Lomize, M. A., Pogozheva, I. D., Joo, H., Mosberg, H. I. & Lomize, A. L. OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res. 40, D370–D376 (2012).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • McGibbon, R. T. et al. MDTraj: a modern open library for the analysis of molecular dynamics trajectories. Biophys. J. 109, 1528–1532 (2015).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • DeLano, W. L. Pymol: an open-source molecular graphics tool. CCP4 http://legacy.ccp4.ac.uk/newsletters/newsletter40/11_pymol.html (2002).

  • Goddard, T. D. et al. UCSF ChimeraX: meeting modern challenges in visualization and analysis. Protein Sci. 27, 14–25 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     



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