O’Donnell, J., Zeppenfeld, D., McConnell, E., Pena, S. & Nedergaard, M. Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. Neurochem. Res. 37, 2496–2512 (2012).
Pacholczyk, T., Blakely, R. D. & Amara, S. G. Expression cloning of a cocaine-and antidepressant-sensitive human noradrenaline transporter. Nature 350, 350–354 (1991).
Torres, G. E., Gainetdinov, R. R. & Caron, M. G. Plasma membrane monoamine transporters: structure, regulation and function. Nat. Rev. Neurosci. 4, 13–25 (2003).
Huang, Y. & Thathiah, A. Regulation of neuronal communication by G protein-coupled receptors. FEBS Lett. 589, 1607–1619 (2015).
Iversen, L. L. Role of transmitter uptake mechanisms in synaptic neurotransmission. Br. J. Pharmacol. 41, 571–591 (1971).
Cheng, M. H. & Bahar, I. Monoamine transporters: structure, intrinsic dynamics and allosteric regulation. Nat. Struct. Mol. Biol. 26, 545–556 (2019).
Ramamoorthy, S., Shippenberg, T. S. & Jayanthi, L. D. Regulation of monoamine transporters: role of transporter phosphorylation. Pharmacol. Ther. 129, 220–238 (2011).
Knable, M. B. & Weinberger, D. R. Dopamine, the prefrontal cortex and schizophrenia. J. Psychopharmacol. 11, 123–131 (1997).
Ramos, B. P. & Arnsten, A. F. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol. Ther. 113, 523–536 (2007).
Azizi, S. A. Monoamines: dopamine, norepinephrine, and serotonin, beyond modulation, “switches” that alter the state of target networks. Neuroscientist 28, 121–143 (2022).
Giros, B. et al. Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine–norepinephrine transporters. J. Biol. Chem. 269, 15985–15988 (1994).
Sesack, S. R., Hawrylak, V. A., Matus, C., Guido, M. A. & Levey, A. I. Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J. Neurosci. 18, 2697–2708 (1998).
Gu, H., Wall, S. C. & Rudnick, G. Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence. J. Biol. Chem. 269, 7124–7130 (1994).
Bonisch, H. & Bruss, M. The norepinephrine transporter in physiology and disease. Handb. Exp. Pharmacol. 175, 485–524 (2006).
National Library of Medicine (US). Drugs and Lactation Database (LactMed) https://www.ncbi.nlm.nih.gov/books/NBK501922/ (2006).
Osland, S. T., Steeves, T. D. & Pringsheim, T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst. Rev. 6, CD007990 (2018).
Agabio, R., Trogu, E. & Pani, P. P. Antidepressants for the treatment of people with co-occurring depression and alcohol dependence. Cochrane Database Syst. Rev. 4, CD008581 (2018).
Owens, M. J., Knight, D. L. & Nemeroff, C. B. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol. Psychiatry 50, 345–350 (2001).
Tatsumi, M., Groshan, K., Blakely, R. D. & Richelson, E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur. J. Pharmacol. 340, 249–258 (1997).
Iversen, L. Neurotransmitter transporters and their impact on the development of psychopharmacology. Br. J. Pharmacol. 147, S82–S88 (2006).
Masand, P. S. & Gupta, S. Long-term side effects of newer-generation antidepressants: SSRIS, venlafaxine, nefazodone, bupropion, and mirtazapine. Ann. Clin. Psychiatry 14, 175–182 (2002).
Bymaster, F. P. et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27, 699–711 (2002).
Maxwell, R. et al. Pharmacological and Biochemical Properties of Drug Substances (American Pharmaceutical Association Academy of Pharmaceutical Sciences, 1981).
Yamashita, A., Singh, S. K., Kawate, T., Jin, Y. & Gouaux, E. Crystal structure of a bacterial homologue of Na+/Cl−-dependent neurotransmitter transporters. Nature 437, 215–223 (2005).
Zhou, Z. et al. LeuT–desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317, 1390–1393 (2007).
Singh, S. K., Yamashita, A. & Gouaux, E. Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448, 952–956 (2007).
Penmatsa, A., Wang, K. H. & Gouaux, E. X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature 503, 85–90 (2013).
Wang, K. H., Penmatsa, A. & Gouaux, E. Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature 521, 322–327 (2015).
Penmatsa, A., Wang, K. H. & Gouaux, E. X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine. Nat. Struct. Mol. Biol. 22, 506–508 (2015).
Pidathala, S., Mallela, A. K., Joseph, D. & Penmatsa, A. Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters. Nat. Commun. 12, 2199 (2021).
Coleman, J. A., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–339 (2016).
Coleman, J. A. & Gouaux, E. Structural basis for recognition of diverse antidepressants by the human serotonin transporter. Nat. Struct. Mol. Biol. 25, 170–175 (2018).
Coleman, J. A. et al. Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport. Nature 569, 141–145 (2019).
Coleman, J. A. et al. Chemical and structural investigation of the paroxetine–human serotonin transporter complex. eLife 9, e56427 (2020).
Plenge, P. et al. The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. Nat. Commun. 12, 5063 (2021).
Yang, D. & Gouaux, E. Illumination of serotonin transporter mechanism and role of the allosteric site. Sci. Adv. 7, eabl3857 (2021).
Billesbolle, C. B. et al. Transition metal ion FRET uncovers K+ regulation of a neurotransmitter/sodium symporter. Nat. Commun. 7, 12755 (2016).
Hasenhuetl, P. S., Freissmuth, M. & Sandtner, W. Electrogenic binding of intracellular cations defines a kinetic decision point in the transport cycle of the human serotonin transporter. J. Biol. Chem. 291, 25864–25876 (2016).
Schmidt, S. G. et al. The dopamine transporter antiports potassium to increase the uptake of dopamine. Nat. Commun. 13, 2446 (2022).
Rudnick, G. & Sandtner, W. Serotonin transport in the 21st century. J. Gen. Physiol. 151, 1248–1264 (2019).
Hellsberg, E. et al. Identification of the potassium-binding site in serotonin transporter. Proc. Natl Acad. Sci. USA 121, e2319384121 (2024).
Wang, N. et al. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell 184, 370–383.e13 (2021).
Yan, R. et al. Structural basis for sterol sensing by Scap and Insig. Cell Rep. 35, 109299 (2021).
Yan, R. et al. A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols. Science 371, eabb2224 (2021).
Yuan, Y. et al. Cryo-EM structure of human glucose transporter GLUT4. Nat. Commun. 13, 2671 (2022).
Zhu, A. et al. Molecular basis for substrate recognition and transport of human GABA transporter GAT1. Nat. Struct. Mol. Biol. 30, 1012–1022 (2023).
Zhang, X. et al. An atomic structure of the human spliceosome. Cell 169, 918–929.e14 (2017).
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).
Sorensen, L. et al. Interaction of antidepressants with the serotonin and norepinephrine transporters: mutational studies of the S1 substrate binding pocket. J. Biol. Chem. 287, 43694–43707 (2012).
Wang, H. et al. Structural basis for action by diverse antidepressants on biogenic amine transporters. Nature 503, 141–145 (2013).
Andersen, J., Kristensen, A. S., Bang-Andersen, B. & Stromgaard, K. Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters. Chem. Commun. 25, 3677–3692 (2009).
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
Andersen, J. et al. Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters. Proc. Natl Acad. Sci. USA 108, 12137–12142 (2011).
Wei, Y. et al. Transport mechanism and pharmacology of the human GlyT1. Cell 187, 1719–1732.e14 (2024).
Singh, I. et al. Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. Cell 186, 2160–2175.e17 (2023).
Singh, S. K., Piscitelli, C. L., Yamashita, A. & Gouaux, E. A competitive inhibitor traps LeuT in an open-to-out conformation. Science 322, 1655–1661 (2008).
Motiwala, Z. et al. Structural basis of GABA reuptake inhibition. Nature 606, 820–826 (2022).
Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).
Lei, J. & Frank, J. Automated acquisition of cryo-electron micrographs for single particle reconstruction on an FEI Tecnai electron microscope. J. Struct. Biol. 150, 69–80 (2005).
Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).
Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).
Afonine, P. V. et al. Real-space refinement in PHENIX for cryo-EM and crystallography. Acta Crystallogr. D Struct. Biol. 74, 531–544 (2018).
Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D Struct. Biol. 75, 861–877 (2019).
Amunts, A. et al. Structure of the yeast mitochondrial large ribosomal subunit. Science 343, 1485–1489 (2014).
Salomon‐Ferrer, R., Case, D. A. & Walker, R. C. An overview of the AMBER biomolecular simulation package. WIREs Comput. Mol. Sci. 3, 198–210 (2012).
Tian, C. et al. ff19SB: amino-acid-specific protein backbone parameters trained against quantum mechanics energy surfaces in solution. J. Chem. Theory Comput. 16, 528–552 (2020).
Dickson, C. J., Walker, R. C. & Gould, I. R. Lipid21: complex lipid membrane simulations with AMBER. J. Chem. Theory Comput. 18, 1726–1736 (2022).
Sprenger, K. G., Jaeger, V. W. & Pfaendtner, J. The general AMBER force field (GAFF) can accurately predict thermodynamic and transport properties of many ionic liquids. J. Phys. Chem. B 119, 5882–5895 (2015).
Valdes-Tresanco, M. S., Valdes-Tresanco, M. E., Valiente, P. A. & Moreno, E. gmx_MMPBSA: a new tool to perform end-state free energy calculations with GROMACS. J. Chem. Theory Comput. 17, 6281–6291 (2021).
Delano, W. L. PyMol: an open-source molecular graphics tool. Protein Crystallogr. 40, 82–92 (2002).
