Conformational dynamics of the human serotonin transporter during substrate and drug binding.
Ingvar R Möller, Marika Slivacka, Anne Kathrine Nielsen, Søren G F Rasmussen, Ulrik Gether, Claus J Loland, Kasper D Rand
Nature Communications April 11, 2019 DOI: 10.1038/s41467-019-09675-z (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Human serotonin transporter (SERT) protein |
| Topics | Serotonin |
| Keywords | Serotonin transporter Drug action Mass spectrometry |
| Citations | 92 |
| Key findings | Binding of co-transported ions (Na+/K+) alters dynamics in regions TM1, EL3, EL4, and TM12, while binding of serotonin and drugs (S-citalopram, cocaine, ibogaine) alters dynamics in TM1, EL3, and EL4 of human SERT. |
Abstract
The serotonin transporter (SERT), a member of the neurotransmitter:sodium symporter family, is responsible for termination of serotonergic signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Its key role in synaptic transmission makes it a major drug target, e.g. for the treatment of depression, anxiety and post-traumatic stress. Here, we apply hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs. Our results reveal significant changes in dynamics in regions TM1, EL3, EL4, and TM12 upon binding co-transported ions (Na+/K+) and ligand-mediated changes in TM1, EL3 and EL4 upon binding 5-HT, the drugs S-citalopram, cocaine and ibogaine. Our results provide a comprehensive direct view of the conformational response of SERT upon binding both biologically relevant substrate/ions and ligands of pharmaceutical interest, thus advancing our understanding of the structure-function relationship in SERT.