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Serotonin 5-HT(2C) Receptor Cys23Ser Single Nucleotide Polymorphism Associates with Receptor Function and Localization In Vitro

A non-synonymous single nucleotide polymorphism of the human serotonin 5-HT(2C) receptor (5-HT(2C)R) gene that converts a cysteine to a serine at amino acid codon 23 (Cys23Ser) appears to impact 5-HT(2C)R pharmacology at a cellular and systems level. We hypothesized that the Cys23Ser alters 5-HT(2C)...

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Detalles Bibliográficos
Autores principales: Land, Michelle A., Chapman, Holly L., Davis-Reyes, Brionna D., Felsing, Daniel E., Allen, John A., Moeller, F. Gerard, Elferink, Lisa A., Cunningham, Kathryn A., Anastasio, Noelle C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853916/
https://www.ncbi.nlm.nih.gov/pubmed/31723224
http://dx.doi.org/10.1038/s41598-019-53124-2
Descripción
Sumario:A non-synonymous single nucleotide polymorphism of the human serotonin 5-HT(2C) receptor (5-HT(2C)R) gene that converts a cysteine to a serine at amino acid codon 23 (Cys23Ser) appears to impact 5-HT(2C)R pharmacology at a cellular and systems level. We hypothesized that the Cys23Ser alters 5-HT(2C)R intracellular signaling via changes in subcellular localization in vitro. Using cell lines stably expressing the wild-type Cys23 or the Ser23 variant, we show that 5-HT evokes intracellular calcium release with decreased potency and peak response in the Ser23 versus the Cys23 cell lines. Biochemical analyses demonstrated lower Ser23 5-HT(2C)R plasma membrane localization versus the Cys23 5-HT(2C)R. Subcellular localization studies demonstrated O-linked glycosylation of the Ser23 variant, but not the wild-type Cys23, may be a post-translational mechanism which alters its localization within the Golgi apparatus. Further, both the Cys23 and Ser23 5-HT(2C)R are present in the recycling pathway with the Ser23 variant having decreased colocalization with the early endosome versus the Cys23 allele. Agonism of the 5-HT(2C)R causes the Ser23 variant to exit the recycling pathway with no effect on the Cys23 allele. Taken together, the Ser23 variant exhibits a distinct pharmacological and subcellular localization profile versus the wild-type Cys23 allele, which could impact aspects of receptor pharmacology in individuals expressing the Cys23Ser SNP.