Identification, expression, and pharmacology of a cys₂₃-ser₂₃ substitution in the human 5-ht_2c receptor gene (htr2c)

The function of brain serotonin-2C (5-HT_2C) receptors, including behavioral and neurochemical responses to 5-HT_2C agonist challenge, has been suggested to be abnormal in individuals with neuropsychiatric disorders. Thus, it is important to identify polymorphisms and functional variants within this gene. Using SSCP analysis, we identified a Cys₂₃-Ser₂₃ substitution (designated 5-HT_2Ccys and 5-HT_2Cser) in the first hydrophobic region of the human 5-HT_2C receptor. Allele frequencies in unrelated Caucasians were 0.13 and 0.87 for 5-HT_2Cser and 5-HT2_Ccys, respectively. DNAs from informative CEPH families were typed for this polymorphism and analyzed with respect to 20 linked markers on the X chromosome. Linkage analysis placed the 5-HT_2C receptor gene (HTR2C) on Xq24. To evaluate whether this amino acid substitution causes a variant function of this receptor, recombinant human 5-HT_2Ccys and 5-HT_2Cser receptors were expressed in Xenopus oocytes and tested for responses to 5-HT using electrophysiological techniques. Concentration-response curves for 5-HT were not significantly different in oocytes expressing either form of the receptor, suggesting that the 5-HT_2Ccys and 5-HT_2Cser receptor proteins may not differ in their responses to serotonin under baseline physiological conditions.