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

Overview

Journal Sci Rep

Specialty Science

Date 2019 Nov 15

PMID 31723224

Citations 2

Authors

Michelle A Land

Holly L Chapman

Brionna D Davis-Reyes

Daniel E Felsing

John A Allen

F Gerard Moeller

Lisa A Elferink

Kathryn A Cunningham

Noelle C Anastasio

Affiliations

Soon will be listed here.

Abstract

A non-synonymous single nucleotide polymorphism of the human serotonin 5-HT receptor (5-HTR) gene that converts a cysteine to a serine at amino acid codon 23 (Cys23Ser) appears to impact 5-HTR pharmacology at a cellular and systems level. We hypothesized that the Cys23Ser alters 5-HTR 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-HTR plasma membrane localization versus the Cys23 5-HTR. 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-HTR 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-HTR 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.

Citing Articles

Association of serotonin receptor gene polymorphisms with anorexia nervosa: a systematic review and meta-analysis.

Bevilacqua A, Santini F, La Porta D, Cimino S Eat Weight Disord. 2024; 29(1):31.

PMID: 38668826 PMC: 11052845. DOI: 10.1007/s40519-024-01659-3.

A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine.

Ma L, Cunningham K, Anastasio N, Bjork J, Taylor B, Arias A Transl Psychiatry. 2022; 12(1):187.

PMID: 35523779 PMC: 9076859. DOI: 10.1038/s41398-022-01934-w.

References

Sodhi M, Burnet P, Makoff A, Kerwin R, Harrison P . RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia. Mol Psychiatry. 2001; 6(4):373-9. DOI: 10.1038/sj.mp.4000920. View

Walstab J, Steinhagen F, Bruss M, Gothert M, Bonisch H . Differences between human wild-type and C23S variant 5-HT2C receptors in inverse agonist-induced resensitization. Pharmacol Rep. 2011; 63(1):45-53. DOI: 10.1016/s1734-1140(11)70397-8. View

Roth J . Cytochemical localization of terminal N-acetyl-D-galactosamine residues in cellular compartments of intestinal goblet cells: implications for the topology of O-glycosylation. J Cell Biol. 1984; 98(2):399-406. PMC: 2113104. DOI: 10.1083/jcb.98.2.399. View

Yamashiro D, Tycko B, Fluss S, Maxfield F . Segregation of transferrin to a mildly acidic (pH 6.5) para-Golgi compartment in the recycling pathway. Cell. 1984; 37(3):789-800. DOI: 10.1016/0092-8674(84)90414-8. View

Egerton A, Ahmad R, Hirani E, Grasby P . Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat. Psychopharmacology (Berl). 2008; 200(4):487-96. DOI: 10.1007/s00213-008-1226-4. View

Lappalainen J, Zhang L, Dean M, Oz M, Ozaki N, Yu D . Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). Genomics. 1995; 27(2):274-9. DOI: 10.1006/geno.1995.1042. View

Cunningham K, Fox R, Anastasio N, Bubar M, Stutz S, Moeller F . Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues. Neuropharmacology. 2011; 61(3):513-23. PMC: 3115535. DOI: 10.1016/j.neuropharm.2011.04.034. View

Lowe M . Structural organization of the Golgi apparatus. Curr Opin Cell Biol. 2010; 23(1):85-93. DOI: 10.1016/j.ceb.2010.10.004. View

Swinford-Jackson S, Anastasio N, Fox R, Stutz S, Cunningham K . Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system. Neuroscience. 2016; 324:50-61. PMC: 4838519. DOI: 10.1016/j.neuroscience.2016.02.052. View

10.

Song G, Yang D, Wang Y, de Graaf C, Zhou Q, Jiang S . Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature. 2017; 546(7657):312-315. DOI: 10.1038/nature22378. View

11.

Reynolds G, Templeman L, Zhang Z . The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29(6):1021-8. DOI: 10.1016/j.pnpbp.2005.03.019. View

12.

Chanrion B, Mannoury la Cour C, Gavarini S, Seimandi M, Vincent L, Pujol J . Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulation of cell surface expression and signal transduction. Mol Pharmacol. 2007; 73(3):748-57. DOI: 10.1124/mol.107.041574. View

13.

Piva F, Giulietti M, Baldelli L, Nardi B, Bellantuono C, Armeni T . Bioinformatic analyses to select phenotype affecting polymorphisms in HTR2C gene. Hum Psychopharmacol. 2011; 26(6):365-72. DOI: 10.1002/hup.1214. View

14.

Huet G, Kim I, de Bolos C, Lo-Guidice J, Moreau O, Hemon B . Characterization of mucins and proteoglycans synthesized by a mucin-secreting HT-29 cell subpopulation. J Cell Sci. 1995; 108 ( Pt 3):1275-85. DOI: 10.1242/jcs.108.3.1275. View

15.

Okada M, Northup J, Ozaki N, Russell J, Linnoila M, Goldman D . Modification of human 5-HT(2C) receptor function by Cys23Ser, an abundant, naturally occurring amino-acid substitution. Mol Psychiatry. 2003; 9(1):55-64. DOI: 10.1038/sj.mp.4001357. View

16.

Kuhn K, Joe A, Meyer K, Reichmann K, Maier W, Rao M . Neuroimaging and 5-HT2C receptor polymorphism: a HMPAO-SPECT study in healthy male probands using mCPP-challenge of the 5-HT2C receptor. Pharmacopsychiatry. 2004; 37(6):286-91. DOI: 10.1055/s-2004-832685. View

17.

Chen Y, Peng Y, Che P, Gannon M, Liu Y, Li L . α(2A) adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction. Proc Natl Acad Sci U S A. 2014; 111(48):17296-301. PMC: 4260556. DOI: 10.1073/pnas.1409513111. View

18.

Lesuffleur T, Capon C, de Bolos C, Kim I, Moreau O, Richet C . Permanent exposure of mucin-secreting HT-29 cells to benzyl-N-acetyl-alpha-D-galactosaminide induces abnormal O-glycosylation of mucins and inhibits constitutive and stimulated MUC5AC secretion. Biochem J. 1998; 334 ( Pt 1):283-95. PMC: 1219690. DOI: 10.1042/bj3340283. View

19.

Felsing D, Anastasio N, Miszkiel J, Gilbertson S, Allen J, Cunningham K . Biophysical validation of serotonin 5-HT2A and 5-HT2C receptor interaction. PLoS One. 2018; 13(8):e0203137. PMC: 6114921. DOI: 10.1371/journal.pone.0203137. View

20.

Vasudevan D, Haltiwanger R . Novel roles for O-linked glycans in protein folding. Glycoconj J. 2014; 31(6-7):417-26. PMC: 4214879. DOI: 10.1007/s10719-014-9556-4. View