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The activity of the serotonin receptor 2C is regulated by alternative splicing

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Abstract

The central nervous system-specific serotonin receptor 2C (5HT2C) controls key physiological functions, such as food intake, anxiety, and motoneuron activity. Its deregulation is involved in depression, suicidal behavior, and spasticity, making it the target for antipsychotic drugs, appetite controlling substances, and possibly anti-spasm agents. Through alternative pre-mRNA splicing and RNA editing, the 5HT2C gene generates at least 33 mRNA isoforms encoding 25 proteins. The 5HT2C is a G-protein coupled receptor that signals through phospholipase C, influencing the expression of immediate/early genes like c-fos. Most 5HT2C isoforms show constitutive activity, i.e., signal without ligand binding. The constitutive activity of 5HT2C is decreased by pre-mRNA editing as well as alternative pre-mRNA splicing, which generates a truncated isoform that switches off 5HT2C receptor activity through heterodimerization; showing that RNA processing regulates the constitutive activity of the 5HT2C system. RNA processing events influencing the constitutive activity target exon Vb that forms a stable double stranded RNA structure with its downstream intron. This structure can be targeted by small molecules and oligonucleotides that change exon Vb alternative splicing and influence 5HT2C signaling in mouse models, leading to a reduction in food intake. Thus, the 5HT2C system is a candidate for RNA therapy in multiple models of CNS disorders.

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Acknowledgements

The work was supported by the NIH (R21NS098186) and the Foundation for Prader–Willi Research.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA

    Stefan Stamm & Samuel B. Gruber

  2. Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA

    Alexander G. Rabchevsky

  3. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    Ronald B. Emeson

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  1. Stefan Stamm
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  2. Samuel B. Gruber
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  3. Alexander G. Rabchevsky
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  4. Ronald B. Emeson
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Correspondence to Stefan Stamm.

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Stamm, S., Gruber, S.B., Rabchevsky, A.G. et al. The activity of the serotonin receptor 2C is regulated by alternative splicing. Hum Genet 136, 1079–1091 (2017). https://doi.org/10.1007/s00439-017-1826-3

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