The expression profile, signaling and neuronal functions of the 5-HT2C receptor makes it a candidate of interest for the treatment of several neuropsychiatric diseases. The encoded ligand-gated G-protein coupled receptor (GPCR) protein responds to cell signaling through several neurotransmitters. Signal transduction through G-proteins is a prominent feature of several eukaryotes. In this review and analysis paper, we provide background literature on the unique biochemical, structural, and pharmacological properties of the 5-HT2c receptor and gene architecture, regulation, RNA editing and association studies of polymorphisms. Also on the evolutionary, and phylogenetic paths. of the 5HT2C gene. We conduct in silico predictions using bioinformatics tools SIFT and POLYPHEN to assess the effect of Cys23ser substitution in the N-terminal extracellular loop. Further, epigenetic analysis of the promoter and regions flanking the exon such as (DNase I Hypersensitivity, enhancer with TF binding site); methylation analysis of promoter (CpG methylation and CpG island); and histone marks with FAIRE. The results suggested that the cys23ser substitution can affect the 3D-protein structure. The additional cysteine amino acids (position-23,235,341) in human receptor could enable additional structural stability to the protein and may have evolved from previous ancestors (various mammals and primates) to aid the modulation of behavioral traits under evolutionary pressure. The alterations in DNA methylation and associated regulatory elements in promoter and upstream could impact gene expression, inactivation, genome stabilization, and inheritance which could have relevance in pathological states in the Central nervous system (CNS).
Author(s) Details:
Kiran Kumar Halagur Bhogegowda
Former Post-doc NCBS, Bangalore. Wilson Garden, Bangalore-560030, affiliated to Nrupathunga University, Bengaluru, 560001, India.
Sajeeda Niketh
Department of Biochemistry, Nrupathunga University, Bengaluru, 560001, India.
Sowmyashree BS
Department of Biotechnology, Nrupathunga University, Bengaluru, 560001, India.
Tenkanidiyooru Ramamoorthy Prashith Kekuda
Department of Microbiology, S.R.N.M College of Applied Science. N.E.S Campus. Balraj urs Road, Shimoga-577201, India.
Recent Global Research Developments in Insights into the 5-HT2C Receptor
Identification of Natural Products as Novel Ligands for the Human 5-HT2C Receptor: This study explores the identification of natural compounds that can act as ligands for the 5-HT2C receptor. Using a combination of molecular docking, affinity mass spectrometry, and in vitro assays, researchers identified several aporphine alkaloids, including (–)-crebanine, which interact with the 5-HT2C receptor [1] .
Contemporary Perspective on 5-HT2C Receptor Function and Its Pharmacological Targeting: This editorial compilation provides a comprehensive overview of the 5-HT2C receptor’s function and its potential as a pharmacological target. It discusses the receptor’s role in various neuropsychiatric disorders and the impact of disease conditions on its expression and function [2] .
Biophysical Validation of Serotonin 5-HT2A and 5-HT2C Receptor Interaction: This research article validates the close interaction between the 5-HT2A and 5-HT2C receptors using biophysical and immunocytochemistry-based approaches. The study highlights the potential cooperative role of these receptors in regulating neural behaviors [3] .
Molecular and Structural Insights into the 5-HT2C Receptor as a Therapeutic Target: This review delves into the structural and molecular mechanisms of the 5-HT2C receptor, especially in the context of substance use disorders (SUD). It discusses recent advancements in understanding the receptor’s function and its potential therapeutic applications [4] .
Editorial: Contemporary Perspective on 5-HT2C Receptor Function and Its Pharmacological Targeting: Another editorial from the same research topic, this article emphasizes the regulatory features of the 5-HT2C receptor, including RNA editing and oligomeric formations. It also covers the receptor’s pharmacological targeting in neuropsychiatric diseases [2] .
References
- Peng, Y., Zhao, S., Wu, Y. et al. Identification of natural products as novel ligands for the human 5-HT2C receptor. Biophys Rep 4, 50–61 (2018). https://doi.org/10.1007/s41048-018-0047-1
- De Deurwaerdère P, Chagraoui A and Cunningham KA (2020) Editorial: Contemporary Perspective on 5-HT2C Receptor Function and Its Pharmacological Targeting. Front. Pharmacol. 11:606414. doi: 10.3389/fphar.2020.606414
- Felsing DE, Anastasio NC, Miszkiel JM, Gilbertson SR, Allen JA, Cunningham KA (2018) Biophysical validation of serotonin 5-HT2A and 5-HT2C receptor interaction. PLoS ONE 13(8): e0203137. https://doi.org/10.1371/journal.pone.0203137
- Ubhayarathna, M., Langmead, C. J., Diepenhorst, N. A., & Stewart, G. D. (2023). Molecular and structural insights into the 5‐HT2C receptor as a therapeutic target for substance use disorders. British Journal of Pharmacology.
