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Review
. 2021 Nov 2;22(21):11910.
doi: 10.3390/ijms222111910.

Tapping into 5-HT3 Receptors to Modify Metabolic and Immune Responses

Helen Irving  1 , Ilona Turek  1 , Christine Kettle  1 , Nor Yaakob  2
Affiliations
Review

Tapping into 5-HT3 Receptors to Modify Metabolic and Immune Responses

Helen Irving et al. Int J Mol Sci. .

Abstract

5-hydroxytryptamine type 3 (5-HT3) receptors are ligand gated ion channels, which clearly distinguish their mode of action from the other G-protein coupled 5-HT or serotonin receptors. 5-HT3 receptors are well established targets for emesis and gastrointestinal mobility and are used as adjunct targets in treating schizophrenia. However, the distribution of these receptors is wider than the nervous system and there is potential that these additional sites can be targeted to modulate inflammatory and/or metabolic conditions. Recent progress in structural biology and pharmacology of 5-HT3 receptors have provided profound insights into mechanisms of their action. These advances, combined with insights into clinical relevance of mutations in genes encoding 5-HT3 subunits and increasing understanding of their implications in patient's predisposition to diseases and response to the treatment, open new avenues for personalized precision medicine. In this review, we recap on the current status of 5-HT3 receptor-based therapies using a biochemical and physiological perspective. We assess the potential for targeting 5-HT3 receptors in conditions involving metabolic or inflammatory disorders based on recent findings, underscoring the challenges and limitations of this approach.

Keywords: 5-HT3 receptor-based therapies; 5-hydroxytryptamine receptors; HTR3 single nucleotide polymorphism; HTR3 variant associations; adipose tissue; chemotherapy induced vomiting and emesis (CINV); inflammation; metabolism; serotonin receptors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic timeline of major discoveries in 5-HT3 receptor biology. 5-HT3 receptors (5-HT3R) are cysteine loop ligand gated ion channels formed by a pentamer arrangement of subunits as shown by the five circles. Initial clinical approval by the US Food and Drug Administration (FDA) of the first generation 5-HT3 receptor antagonist ondansetron and the second-generation antagonist palonosetron are also indicated. From the early 2000s, several single nucleotide polymorphisms (SNPs) and other polymorphisms have been associated with various clinical disorders. Further details are outlined in the text.
Figure 2
Figure 2
Architecture of 5-HT3 receptors. (A) Homology model of the human 5-HT3AC receptor assembled in the A3C2 stoichiometry showing membrane spanning side and central pore views (maroon = A and green = C subunits). Examples of proposed binding sites for competitive, non-competitive, and dual acting antagonists (labeled 1–3), and allosteric modulators (indicated with 4). The model is from [153] where A and C subunits were created from the mouse 5-HT3A receptor structure [139] as they have 95% and 58% homology with the mouse A subunit, respectively. (B) Schematic diagram of a single 5-HT3 receptor subunit showing the different domains and extracellular A–F loops (bolded in blue). A Clustal omega alignment was done on the human 5-HT3 receptor subunit protein sequences obtained from NCBI [154] and this is shown for the Cys-loop (yellow box), membrane-spanning α-helices of transmembrane domains 1 to 4 (TM1-TM4) (brown and orange boxes), the triple R region of the intracellular loop involved in pentamer assembly [155] and the low conductance associated with A homomer receptors [156] (purple box). Accession numbers: NP_000860 (A subunit), NP_006019 (B subunit), NP_570126 (C subunit), NP_001157118 (D subunit), and NP_872395 (E subunit). Identical residues are indicated with an asterisk (*), conserved residues with a colon (:), and semi-conserved residues with a full stop (.). Image drawn in Adobe Illustrator.
Figure 3
Figure 3
Roles of 5-HT3 receptors in diseases and metabolic disorders. Microbiota and their metabolites present in the lumen of the gut can affect the epithelial cells and any dendritic cells to modulate local immune function and induce enterochromaffin (EC) cells to secrete serotonin (5-HT, shown as green circles) that enters the circulation. Visceral stimulation via the sympathetic nervous system induces production of serotonin by EC cells. The enteric nervous system, consisting of submucosal plexus underneath the epithelial cells lining, interacts directly with layers of the gut wall and parasympathetic, spinal, and vagal nerves to enable bidirectional communication with the central nervous system. 5-HT release from the ECs activates 5-HT3 receptors on enteric neurons, vagal and spinal afferents, and these in turn relay input to the dorsal root ganglia and the brain stem. Overactivation of the chemoreceptor complex in the brainstem can lead to emesis and the processes also contribute to functional gastrointestinal (GI) disorders, such as irritable bowel syndrome, and nociception. Neuropsychiatric disorders like depression and schizophrenia are affected by disturbed 5-HT3 receptor signaling in the limbic region of the brain. Increased circulatory 5-HT is associated with increases in production of cytokines (shown as magenta circles), and sometimes nociception. In addition, these circulatory changes in 5-HT can potentially modify adipose function where brown adipose cells decrease thermogenesis normally raised by sympathetic activation, although this has mainly been studied using rodent models. By activating 5-HT2 and 5-HT3 receptors, 5-HT in the pancreas enhances ß cells to secrete more insulin, which acts on α cells to inhibit glucagon secretion. Physiological levels of 5-HT released by ß cells in response to glucose also lead to decrease in glucagon secretion and this effect is mediated by 5-HT1 receptor on α cells. For further details see the text (Section 5 and Section 6). Image drawn in Adobe Illustrator with brain image created by Hugh Guiney (CC BY-SA 3.0 https://creativecommons.org/licenses/by-sa/3.0, accessed on 25 October 2021), via Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Human-brain.SVG, accessed on 25 October 2021) and red blood cells (https://commons.wikimedia.org/wiki/File:Blausen_0761_RedBloodCells.png, accessed on 25 October 2021) created by [248].
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