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.

Highlights

  • Depression and anxiety are the first and sixth highest causes of burden of disability worldwide, respectively (Baxter et al, 2013; Ferrari et al, 2013; World Health Organisation, 2017)

  • We focus on the role the cellular process of endocytosis, serotonin receptors and serotonin transporter (SERT) in the development and treatment of depression and anxiety, but it is likely the endocytic processes we highlight are applicable to many receptors and transporters implicated in the development or treatment of these conditions

  • Endocytosis is clearly central to the regulation of serotonin signaling, SERT, the therapeutic response to hallucinogens, Selective serotonin reuptake inhibitors (SSRIs) function and the function of novel antidepressant compounds

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Summary

INTRODUCTION

Depression and anxiety are the first and sixth highest causes of burden of disability worldwide, respectively (Baxter et al, 2013; Ferrari et al, 2013; World Health Organisation, 2017). Monoamine (neurotransmitters/hormones such as dopamine, serotonin and noradrenaline) transporters are implicated in the treatment of depression and anxiety, with SSRIs targeting the serotonin transporter (SERT), serotonin noradrenaline reuptake inhibits (SNRIs) targeting both SERT and the noradrenaline transporter (NET) and triple uptake inhibitors targeting all three transporters, preventing the uptake of serotonin, dopamine and noradrenaline into the cell (Lucki and O’Leary, 2004; Zhou, 2004). Other transporters such as ERICH3, which acts as a transporter for loading serotonin into vesicles for release from the cell, have been implicated in antidepressant resistance, with a single nucleotide polymorphism identified in SSRI resistant patients that abolished ERICH 3 transport activity (Gupta et al, 2016; Liu et al, 2020). SSRIs block function, antidepressant and anxiolytic effects SSRIs decrease whole blood serotonin levels (human), increase brain levels (rodent models)

CONCLUSIONS
Findings
DATA AVAILABILITY STATEMENT
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