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. 2022 Feb 24:15:804592.
doi: 10.3389/fncel.2021.804592. eCollection 2021.

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

Nikita Deo  1 , Gregory Redpath  2
Affiliations

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

Nikita Deo et al. Front Cell Neurosci. .

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.

Keywords: anxiety; depression; endocytosis; serotonin receptor; serotonin transporter.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Serotonin system involvement in depression and anxiety. (A) 5-HT1A autoreceptors expressed in serotonergic neurons have contrasting roles in depression and anxiety, with increased 5-HT1A signaling potentially increasing depression and decreased signaling increasing anxiety. (B) 5-HT2A signaling induced by serotonin and CRF leads to an increased anxiety response in mice, while hallucinogen signaling through 5-HT2A potentially leads to decreased depression and anxiety symptoms in human patients. (C) SERT transport of serotonin from the extracellular space to inside the cell limits serotonin receptor signaling, with SERT over-activity potentially being causative of depression. SSRIs block the function of SERT, leading to serotonin accumulation in the extracellular space, enabling enhanced serotonin receptor signaling and alleviation of depression symptoms.
Figure 2
Figure 2
Serotonin system endocytic trafficking. (A) 5-HT1A endocytosis is induced by serotonin and is clathrin, dynamin and β-arrestin1 dependent for both autoreceptors and heteroreceptors. Following endocytosis, 5-HT1A is recycled via Rab4 and Rab11-depednent pathways, (this has not been directly demonstrated for 5-HT1A autoreceptors but is consistent with available data, grayed arrow). 5-HT1A autoreceptor endocytosis is induced by serotonin, the SSRI fluoxetine and other pharmacological compounds and leads to rapid endocytic trafficking (double arrows), while 5-HT1A heteroreceptor endocytosis is slower and induced only be serotonin. Endosomal signaling has not been directly demonstrated for 5-HT1A but appears to occur based on pharmacological studies (question mark). (B) 5-HT2A endocytosis is clathrin, dynamin and β-arrestin2 dependent in response to both serotonin and LSD binding. Serotonin and LSD induce differential phosphorylation at the plasma membrane. Following serotonin induced endocytosis, 5-HT2A endosomal sorting leads to Rab4 and Rab11-dependent recycling. The effect of LSD on 5-HT2A endosomal signaling and sorting is unknown (grayed arrow, question marks). (C) SERT endocytosis is presumable clathrin-dependent and demonstrated to be dynamin-dependent. Following endocytosis, SERT can be sorted to the Rab7+ late endosome for lysosomal degradation or can potentially be sorted for Rab11-dependent recycling via interaction with flotillin. The SSRI sertraline induces dynamin-independent endocytosis of SERT, following which the endosomal sorting is unexplored (grayed arrow, question mark).
Figure 3
Figure 3
Hypothetical model of the effect of SNPs, transcript and protein expression changes on serotonin receptor and transporter endocytic trafficking. (A) Reduced PKC phosphorylation will reduce 5-HT2A plasma membrane signaling and β-arrestin recruitment. Reduced β-arrestin1 and 2 levels will reduce CME of both 5-HT1A and 5-HT2A. Further, increased PICALM expression inhibits clathrin-coated pit formation, and PACSIN3 mutations may impair dynamin recruitment, further reducing CME. DENND1A/B mutations could impair coupling of CME to Rab5+ sorting endosomes, reducing uptake, downstream receptor sorting and potential endosomal signaling. Finally, reduced Rab4B expression will prevent rapid recycling of 5-HT1A and 5-HT2A, reducing the potential for rapid resensitization following serotonin-induced endocytosis. (B) Increased PICALM expression, PACSIN3 and DENND1A/B mutations are likely to impair CME of SERT. However, PACSIN2 and Rac1 over-expression could induce CIE of SERT by enhancing actin branching, leading to increased clathrin-independent carrier formation. Following CIE, increased Rab5 and Rab7, expression could increase early to late endosomal trafficking of SERT, following which increased SNX27 expression would salvage SERT from degradation and boost recycling. Alternately, increased EHD1 and flotillin expression would increase sorting of SERT from Rab5+ sorting endosomes to Rab11+ recycling endosomes, further enhancing SERT recycling.
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