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Characterization of genetic variation in the human 5HT Type 2A G-protein coupled receptor (GPCR) Harvey, Layne Joseph


Human serotonin type 2A (5HT2A) receptors are members of the large class of proteins known as G-protein coupled receptors (GPCRs). These receptors are implicated in a variety of human disorders including schizophrenia, anxiety, depression, migraine and * obesity. Recently several allelic variations in the 5HT2A receptor have been identified and attempts have been made to implicate these mutations in the etiology of schizophrenia as well as the variability in patient response to neuroleptic drugs. The objective of this work was to determine if these allelic variants in the 5HT2 receptors affect the potency of the agonist serotonin, the typical antagonist loxapine, and the atypical antagonist clozapine. In this study four naturally occurring polymorphisms, (T25N, I197V, A447V, and H452Y) were generated by site directed mutagenesis in the human 5HT2A gene. The activity of the 5HT2A wild type and mutant receptors was investigated using an in-vitro functional GPCR assay. This assay measures G-protein receptor activity when challenged with agonists or antagonists. The results indicated that the I197V missense variant required a two fold higher concentration of clozapine to inhibit serotonin receptor activation when compared to the wildtype receptor. The I197V variant had no effect on serotonin potency or on the potency of loxapine. This study also indicated that there was no change in potency for the T25N, A447V and H452Y variants K when challenged with the agonist serotonin or the antagonists loxapine and clozapine.

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