An emerging therapeutic strategy for major depressive disorder: targeting the protein-protein interactions

Major depressive disorder (MDD) is a highly heterogeneous psychiatric condition. For decades, drugs targeting serotonin transporter (SERT), such as selective serotonin reuptake inhibitors (SSRIs), have been the mainstay of treatment. However, SSRI antidepressants face significant limitations. This paper discusses the mechanistic defects of conventional antidepressants that directly target serotonin (5-HT) synthesis, degradation, and reuptake and the dual-role dilemma of the 5-HT_1A receptors in the neuropsychopharmacology. In addition, recent findings of regional regulation of SERT by protein-protein interactions (PPIs) open up a promising strategy for future antidepressant development. These PPIs specifically and rapidly regulate SERT capability for 5-HT uptake by modulating its membrane trafficking under physiological conditions. Agents disrupting the SERT-neuronal nitric oxide synthase (nNOS) or soluble guanylate cyclase (sGC) interaction are highlighted as examples to illustrate their mechanism of action by which they selectively deactivate the 5-HT_1A autoreceptors in the dorsal raphe nucleus (DRN) without directly affecting the postsynaptic 5-HT_1A heteroreceptors in 5-HT projection areas. Consequently, these agents enhance 5-HT release in the hippocampus and cortex and produce a fast-onset antidepressant-like activity in depressive animal models. Thus, this emerging strategy can achieve a regional, precise, rapid, and fine-tuning regulation of 5-HT uptake activity by modulating the interactions between SERT and its regulatory proteins in the DRN, while avoiding dysregulation of the essential neurological functions in other brain regions. Targeting the PPI interfaces rather than the transporter itself represents a paradigm shift from the conventional pharmacological approaches to a novel strategy for the precise control of the serotonergic system.