Abstract
The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake. SERT activity is modulated by antidepressants, e.g., S-citalopram and imipramine, to alleviate symptoms of depression and anxiety. SERT crystal structures reveal two S-citalopram binding pockets in the central binding (S1) site and the extracellular vestibule (S2 site). In this study, our combined in vitro and in silico analysis indicates that the bound S-citalopram or imipramine in S1 is allosterically coupled to the ligand binding to S2 through altering protein conformations. Remarkably, SERT inhibitor Lu AF60097, the first high-affinity S2-ligand reported and characterized here, allosterically couples the ligand binding to S1 through a similar mechanism. The SERT inhibition by Lu AF60097 is demonstrated by the potentiated imipramine binding and increased hippocampal serotonin level in rats. Together, we reveal a S1-S2 coupling mechanism that will facilitate rational design of high-affinity SERT allosteric inhibitors.
Highlights
The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake
To examine whether ligand binding to S1 would induce conformational changes of SERT that allosterically affect ligand binding to S237, we first evaluated whether the inhibitory potency of a S2-bound ligand can be differentially affected by the identity of the S1-bound ligand
We found that the allosteric potency of S2:S-CIT was 29-fold higher in the presence of S1:[3H]S-CIT than in the presence of S1:[3H]IMI (Fig. 1b, Table 1)
Summary
The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake. The selective serotonin reuptake inhibitors (SSRIs), such as S-citalopram (S-CIT) (Fig. 1a), sertraline and paroxetine, are currently used to treat depression, anxiety, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) among others[7]. The tricyclic antidepressants, such as imipramine (IMI) (Fig. 1a) and amitriptyline, and the multimodal antidepressants vilazodone and vortioxetine[8], target SERT. A [3H]Ligand dissociation T 1⁄2 ratio (k[cpd]/kbuf) a Imipramine
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