{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The serotonin 5A receptor (HTR5A) has emerged as a versatile modulator in both central and peripheral systems. Cloned as a 357–amino acid protein that is predominantly expressed in the brain, HTR5A shows a pharmacological profile similar to its rodent homologs, with high‐affinity binding to ergot alkaloids, underscoring its potential role in neurotransmission."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In neurodevelopment and behavior, genetic variations and differential expression of HTR5A have been implicated in autism spectrum disorder and mood regulation, with certain polymorphisms and epigenetic modifications being associated with altered risk for autism and mood disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, investigations in schizophrenia have identified specific single nucleotide polymorphisms in HTR5A that correlate with the disease and with measures of executive function"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while studies in personality research suggest that HTR5A expression levels may be linked to traits such as openness and, by extension, to broader neurobehavioral phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its established roles in brain function, HTR5A is increasingly recognized for its involvement in peripheral physiology. Genetic studies have associated sequence variants in HTR5A with elevated plasma triglyceride levels, suggesting an as-yet–unappreciated interface between central serotonergic signaling and metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In line with this, cortisol has been shown to up-regulate the expression of HTR5A in adipocyte and macrophage cultures, contributing to enhanced adipogenesis under stress conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the realm of oncology, HTR5A has garnered attention as a promising therapeutic target. In prostate cancer, antagonists of the 5-HT5A receptor were found to suppress androgen receptor activity via protein kinase A signaling, while differential HTR5A expression has been reported in SPOP-mutant prostate tumors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Similarly, in breast cancer models, selective antagonism of HTR5A reduced the frequency of tumor-initiating cells and enhanced the efficacy of chemotherapy, highlighting its potential role in targeting cancer stem-like cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Additional studies indicate that HTR5A is also engaged in the modulation of stress and fear responses. Differential methylation of the HTR5A gene has been observed in animal models exposed to prenatal or acute stress, and its altered expression has been linked to variations in fear memory and behavioral reactivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Notably, decreased HTR5A expression in certain avian models correlates with heightened neophobic behavior, suggesting that HTR5A may contribute to the regulation of risk-taking and exploratory traits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, emerging data in developmental neuroscience show that HTR5A is expressed in glial populations within human cortical spheroids and avian raphe nuclei, implicating the receptor in the shaping of neural circuits during early brain development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " There is also preliminary evidence hinting at a role for HTR5A in modulating cardiac sympathetic neurotransmission."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings portray HTR5A as a multifunctional serotonin receptor with diverse roles ranging from the fine-tuning of neuronal signaling and behavior to the regulation of metabolic pathways and tumor biology.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "S Rees, I den Daas, S Foord, et al. 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