Serotonin Receptor and Transporter Endocytosis Is an Important Factor in the Cellular Basis of Depression and Anxiety

Abstract

Depression and anxiety are common, debilitating psychiatric conditions affecting millions of people throughout the world. Current treatments revolve around selective serotonin reuptake inhibitors (SSRIs), yet these drugs are only moderately effective at relieving depression. Moreover, up to 30% of sufferers are SSRI non-responders. Endocytosis, the process by which plasma membrane and extracellular constituents are internalized into the cell, plays a central role in the regulation of serotonin (5-hydroxytryptophan, 5-HT) signaling, SSRI function and depression and anxiety pathogenesis. Despite their therapeutic potential, surprisingly little is known about the endocytosis of the serotonin receptors (5-HT receptors) or the serotonin transporter (SERT). A subset of 5-HT receptors are endocytosed by clathrin-mediated endocytosis following serotonin binding, while for the majority of 5-HT receptors the endocytic regulation is not known. SERT internalizes serotonin from the extracellular space into the cell to limit the availability of serotonin for receptor binding and signaling. Endocytosis of SERT reduces serotonin uptake, facilitating serotonin signaling. SSRIs predominantly inhibit SERT, preventing serotonin uptake to enhance 5-HT receptor signaling, while hallucinogenic compounds directly activate specific 5-HT receptors, altering their interaction with endocytic adaptor proteins to induce alternate signaling outcomes. Further, multiple polymorphisms and transcriptional/proteomic alterations have been linked to depression, anxiety, and SSRI non-response. In this review, we detail the endocytic regulation of 5-HT receptors and SERT and outline how SSRIs and hallucinogenic compounds modulate serotonin signaling through endocytosis. Finally, we will examine the deregulated proteomes in depression and anxiety and link these with 5-HT receptor and SERT endocytosis. Ultimately, in attempting to integrate the current studies on the cellular biology of depression and anxiety, we propose that endocytosis is an important factor in the cellular basis of depression and anxiety. We will highlight how a thorough understanding 5-HT receptor and SERT endocytosis is integral to understanding the biological basis of depression and anxiety, and to facilitate the development of a next generation of specific, efficacious antidepressant treatments.

Transcriptional landscape of the dorsal raphe serotonin neurons rendering stress resiliency

“…Surprisingly, we found the decreased expression of 5-HT 1B R in the DRN of S100a10 knockdown mice, even though S100a10 was predicted to be involved only in membrane trafficking of 5-HT 1B R and not to affect its expression level. This decrease may be due to the degradation of internalized GPCR in lysosomes through ubiquitination or other pathways [71][72][73] . Collectively, our study uncovered the role of S100a10 in DRN serotonin neurons, one of the most critical components of the pathophysiology of MDD.…”

Psilocin fosters neuroplasticity in iPSC-derived human cortical neurons

“…"Brain network resetting" 1 by psilocybin , i.e. the restoration of neuronal and synaptic dysfunction associated with the pathophysiology of mental disorders [41][42][43][44][45] , could be achieved by stimulating signaling pathways associated with neuroplasticity and BDNF signaling 24,41 . So far, experimental evidence for this hypothesis is based on data from non-human model organisms.…”

“…Interestingly, pychedelics have been already shown to reduce 5-HT2A-R density in animal models 35,43,44. We see a decrease in receptor surface density, prevented by inhibiting the GTPase dynamin arguing that clathrin-mediated endocytosis is involved in this process, which suggests internalization of cell surface-located 5-HT2A-R. Given the potential of psychedelics to diffuse across cell membranes and to activate intracellular pathways 23 , enhanced internalization of 5-HT2A-R may result in stronger intracellular signaling processes caused by the combination of retrograde trafficking and the activation of internally residing receptors adding both to serotonin-independent and psychedelic-dependent signaling strength 45 .…”

Anxiety in oncology outpatients is associated with perturbations in pathways identified in anxiety focused network pharmacology research

“…The neuroactive ligand-receptor interaction pathway illustrates various ligand-receptor interactions that are critical components of cellular communication processes (e.g., proliferation, apoptosis) and cellular homeostasis [ 43 ]. This pathway includes a number of neurotransmitters associated with anxiety (e.g., 5-hydroxytryptamine [ 44 ], dopamine [ 45 ]) and that it was identified across the eight network pharmacology studies [ 15 – 22 ] suggests that it is an important mechanistic pathway for anxiety.…”