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

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.