Silverberg, A. B., Shah, S. D., Haymond, M. W. & Cryer, P. E. Norepinephrine: hormone and neurotransmitter in man. Am. J. Physiol. 234, E252 (1978).
Pacholczyk, T., Blakely, R. D. & Amara, S. G. Expression cloning of a cocaine-and antidepressant-sensitive human noradrenaline transporter. Nature 350, 350–354 (1991).
Mandela, P. & Ordway, G. A. The norepinephrine transporter and its regulation. J. Neurochem. 97, 310–333 (2006).
Kristensen, A. S. et al. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol. Rev. 63, 585–640 (2011).
Brust, A. et al. χ-Conopeptide pharmacophore development: toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain. J. Med. Chem. 52, 6991–7002 (2009).
Llorca-Torralba, M., Borges, G., Neto, F., Mico, J. A. & Berrocoso, E. Noradrenergic locus coeruleus pathways in pain modulation. Neuroscience 338, 93–113 (2016).
Pertovaara, A. Noradrenergic pain modulation. Prog. Neurobiol. 80, 53–83 (2006).
Berridge, C. W., Schmeichel, B. E. & España, R. A. Noradrenergic modulation of wakefulness/arousal. Sleep Med. Rev. 16, 187–197 (2012).
Sapolsky, R. M., Romero, L. M. & Munck, A. U. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr. Rev. 21, 55–89 (2000).
Jansen, A. S., Nguyen, X. V., Karpitskiy, V., Mettenleiter, T. C. & Loewy, A. D. Central command neurons of the sympathetic nervous system: basis of the fight-or-flight response. Science 270, 644–646 (1995).
Bobb, A. J. et al. Support for association between ADHD and two candidate genes: NET1 and DRD1. Am. J. Med. Genet. B 134, 67–72 (2005).
Lake, C. R. et al. High plasma norepinephrine levels in patients with major affective disorder. Am. J. Psychiatry 139, 1315–1318 (1982).
Bohn, L. M., Xu, F., Gainetdinov, R. R. & Caron, M. G. Potentiated opioid analgesia in norepinephrine transporter knock-out mice. J. Neurosci. 20, 9040–9045 (2000).
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).
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. & 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., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–339 (2016).
Coleman, J. A. et al. Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport. Nature 569, 141–145 (2019).
Plenge, P. et al. The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. Nat. Commun. 12, 5063 (2021).
Paczkowski, F. A., Sharpe, I. A., Dutertre, S. & Lewis, R. J. χ-Conotoxin and tricyclic antidepressant interactions at the norepinephrine transporter define a new transporter model. J. Biol. Chem. 282, 17837–17844 (2007).
Sharpe, I. A. et al. Two new classes of conopeptides inhibit the α1-adrenoceptor and noradrenaline transporter. Nat. Neurosci. 4, 902–907 (2001).
Sharpe, I. A. et al. Inhibition of the norepinephrine transporter by the venom peptide χ-MrIA: site of action, Na+ dependence, and structure–activity relationship. J. Biol. Chem. 278, 40317–40323 (2003).
Zhang, Y. W., Turk, B. E. & Rudnick, G. Control of serotonin transporter phosphorylation by conformational state. Proc. Natl Acad. Sci. USA 113, E2776–E2783 (2016).
Ramamoorthy, S., Shippenberg, T. S. & Jayanthi, L. D. Regulation of monoamine transporters: role of transporter phosphorylation. Pharmacol. Ther. 129, 220–238 (2011).
Hillhouse, T. M. & Porter, J. H. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp. Clin. Psychopharmacol. 23, 1–21 (2015).
Hahn, M. K., Robertson, D. & Blakely, R. D. A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters. J. Neurosci. 23, 4470–4478 (2003).
Kurian, M. A. et al. Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia. J. Clin. Invest. 119, 1595–1603 (2009).
Kurian, M. A. et al. Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. Lancet Neurol. 10, 54–62 (2011).
Beerepoot, P., Lam, V. M. & Salahpour, A. Pharmacological chaperones of the dopamine transporter rescue dopamine transporter deficiency syndrome mutations in heterologous cells. J. Biol. Chem. 291, 22053–22062 (2016).
Shahsavar, A. et al. Structural insights into the inhibition of glycine reuptake. Nature 591, 677–681 (2021).
Motiwala, Z. et al. Structural basis of GABA reuptake inhibition. Nature 606, 820–826 (2022).
Melikian, H. E., Ramamoorthy, S., Tate, C. G. & Blakely, R. D. Inability to N-glycosylate the human norepinephrine transporter reduces protein stability, surface trafficking, and transport activity but not ligand recognition. Mol. Pharmacol. 50, 266–276 (1996).
Sogawa, C. et al. C-terminal region regulates the functional expression of human noradrenaline transporter splice variants. Biochem. J. 401, 185–195 (2007).
Bauman, P. A. & Blakely, R. D. Determinants within the C-terminus of the human norepinephrine transporter dictate transporter trafficking, stability, and activity. Arch. Biochem. Biophys. 404, 80–91 (2002).
Yang, D. & Gouaux, E. Illumination of serotonin transporter mechanism and role of the allosteric site. Sci. Adv. 7, eabl3857 (2021).
Lewis, R. J., Alewood, P. F., Alewood, D. & Palant, E. Type II chi-conotoxin peptides (noradrenaline transporter inhibitors). US Patent US7507717B2 (2009).
Nilsson, K. P. R. et al. Solution structure of χ-conopeptide MrIA, a modulator of the human norepinephrine transporter. Pept. Sci. 80, 815–823 (2005).
Sharpe, I. A. et al. Inhibition of the norepinephrine transporter by the venom peptide chi-MrIA. Site of action, Na+ dependence, and structure-activity relationship. J. Biol. Chem. 278, 40317–40323 (2003).
Gu, H. H., Wall, S. & Rudnick, G. Ion coupling stoichiometry for the norepinephrine transporter in membrane vesicles from stably transfected cells. J. Biol. Chem. 271, 6911–6916 (1996).
Ramamoorthy, S. et al. Expression of a cocaine-sensitive norepinephrine transporter in the human placental syncytiotrophoblast. Biochemistry 32, 1346–1353 (1993).
Koldsø, H. et al. Unbiased simulations reveal the inward-facing conformation of the human serotonin transporter and Na(+) ion release. PLoS Comput. Biol. 7, e1002246 (2011).
Felts, B. et al. The two Na+ sites in the human serotonin transporter play distinct roles in the ion coupling and electrogenicity of transport. J. Biol. Chem. 289, 1825–1840 (2014).
Ascher, J. A. et al. Bupropion: a review of its mechanism of antidepressant activity. J. Clin. Psychiatry 56, 395–401 (1995).
Shalabi, A. R., Walther, D., Baumann, M. H. & Glennon, R. A. Deconstructed analogues of bupropion reveal structural requirements for transporter inhibition versus substrate-induced neurotransmitter release. ACS Chem. Neurosci. 8, 1397–1403 (2017).
Schmidt, A. W., Lebel, L. A., Howard, H. R. & Zorn, S. H. Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur. J. Pharmacol. 425, 197–201 (2001).
Cross, A. J. et al. Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models. Br. J. Pharmacol. 173, 155–166 (2016).
Hong, W. C. & Amara, S. G. Membrane cholesterol modulates the outward facing conformation of the dopamine transporter and alters cocaine binding. J. Biol. Chem. 285, 32616–32626 (2010).
Zeppelin, T., Ladefoged, L. K., Sinning, S., Periole, X. & Schiøtt, B. A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition. PLoS Comput. Biol. 14, e1005907 (2018).
Veber, D. F. et al. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45, 2615–2623 (2002).
Yu, R. et al. Enhanced activity against multidrug-resistant bacteria through coapplication of an analogue of tachyplesin I and an inhibitor of the QseC/B signaling pathway. J. Med. Chem. 63, 3475–3484 (2020).
Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).
Zhang, K. Gctf: real-time CTF determination and correction. J. Struct. Biol. 193, 1–12 (2016).
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).
Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010).
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).
DeLano, W. L. Pymol: An open-source molecular graphics tool. CCP4 Newsl. Protein Crystallogr. 40, 82–92 (2002).
Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).