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

Depression and anxiety affect millions globally, and current treatments like selective serotonin reuptake inhibitors (SSRIs) are only moderately effective, with up to 30% of patients not responding. Endocytosis—the process cells use to internalize surface materials—regulates serotonin signaling, SSRI function, and the development of these disorders. The serotonin transporter (SERT) removes serotonin from outside cells, limiting receptor activation, while its own endocytosis reduces uptake and boosts signaling. SSRIs block SERT to enhance serotonin receptor signaling, whereas hallucinogenic compounds directly activate certain serotonin receptors, altering endocytosis and signaling. Genetic and protein changes are linked to depression, anxiety, and SSRI non-response. This review argues that understanding endocytosis of serotonin receptors and SERT is key to grasping the biology of these conditions and developing better antidepressants.

Study at a glance

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.