October 2025 - Ralph Gradisch

Dr. Ralph Gradisch

MedUni Wien RESEARCHER OF THE MONTH October 2025

The serotonin transporter (SERT) regulates neurotransmission by clearing extracellular serotonin after synaptic release, thereby maintaining spatial and temporal control of serotonergic signaling and homeostasis. Clinically used drugs inhibit this process by trapping SERT in the transport cycle, whereas illicit drugs of abuse such as amphetamines drive reverse transport, leading to serotonin efflux. Both mechanisms elevate extracellular serotonin levels. In this study, we combined molecular dynamics simulations with biochemical assays and employed a homologous series of serotonin analogues to dissect the coupling mechanism between the substrate and SERT triggering its reuptake. Free-energy analyses revealed that only substrates bound within the scaffold domain effectively initiate SERT occlusion through long-range electrostatic interactions targeting the bundle domain. These spatial constraints establish the structural basis that differentiates substrates from inhibitors and highlight new opportunities for rational drug design.

Selected Literature

1. Gradisch, R. et al. Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors. Nat Commun 15, 417 (2024).

2. Berger, M., Gray, J. A. & Roth, B. L. The Expanded Biology of Serotonin. Annu. Rev. Med. 60, 355–366 (2009).

3. Masson, J., Emerit, M. B., Hamon, M. & Darmon, M. Serotonergic signaling: multiple effectors and pleiotropic effects. Wiley Interdiscip. Rev. Membr. Transp. Signal. 1, 685–713 (2012).

4. Murphy, D. L. Serotonin Transporter: Gene, Genetic Disorders, and Pharmacogenetics. Mol. Interv. 4, 109–123 (2004).

5. Lin, Z. & Madras, B. K. Human Genetics and Pharmacology of Neurotransmitter Transporters. in 327–371 (2006). doi:10.1007/3-540-29784-7_16.

6. Kristensen, A. S. et al. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol. Rev. 63, 585–640 (2011).

7. Sitte, H. H. & Freissmuth, M. Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol. Sci. 36, 41–50 (2015).

8. Jardetzky, O. Simple Allosteric Model for Membrane Pumps. Nature 211, 969–970 (1966).

9. Coleman, J. A., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–9 (2016).

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

11. Yang, D. & Gouaux, E. Illumination of serotonin transporter mechanism and role of the allosteric site. Sci. Adv. 7, (2021).