Conformational dynamics of the human serotonin transporter during substrate and drug binding.

The serotonin transporter (SERT) clears serotonin from the synapse, making it a key target for antidepressants and other drugs. Using hydrogen-deuterium exchange mass spectrometry, the authors mapped changes in SERT's shape and flexibility when it binds sodium and potassium ions, the neurotransmitter serotonin, and the drugs S-citalopram, cocaine, and ibogaine. Binding altered dynamics in specific structural regions: TM1, EL3, EL4, and TM12 for ions, and TM1, EL3, and EL4 for the other ligands. These results offer a direct view of how SERT responds to both natural substrates and pharmaceutical compounds, deepening understanding of its structure and function.

Study at a glance

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.