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

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...

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Main Author: Harvey, Layne Joseph
Format: Others
Language:English
Published: 2009
Online Access:http://hdl.handle.net/2429/13932
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spelling ndltd-UBC-oai-circle.library.ubc.ca-2429-139322018-01-05T17:37:02Z 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. Science, Faculty of Zoology, Department of Graduate 2009-10-17T21:12:17Z 2009-10-17T21:12:17Z 2002 2002-11 Text Thesis/Dissertation http://hdl.handle.net/2429/13932 eng For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. 4373499 bytes application/pdf
collection NDLTD
language English
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description 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. === Science, Faculty of === Zoology, Department of === Graduate
author Harvey, Layne Joseph
spellingShingle Harvey, Layne Joseph
Characterization of genetic variation in the human 5HT Type 2A G-protein coupled receptor (GPCR)
author_facet Harvey, Layne Joseph
author_sort Harvey, Layne Joseph
title Characterization of genetic variation in the human 5HT Type 2A G-protein coupled receptor (GPCR)
title_short Characterization of genetic variation in the human 5HT Type 2A G-protein coupled receptor (GPCR)
title_full Characterization of genetic variation in the human 5HT Type 2A G-protein coupled receptor (GPCR)
title_fullStr Characterization of genetic variation in the human 5HT Type 2A G-protein coupled receptor (GPCR)
title_full_unstemmed Characterization of genetic variation in the human 5HT Type 2A G-protein coupled receptor (GPCR)
title_sort characterization of genetic variation in the human 5ht type 2a g-protein coupled receptor (gpcr)
publishDate 2009
url http://hdl.handle.net/2429/13932
work_keys_str_mv AT harveylaynejoseph characterizationofgeneticvariationinthehuman5httype2agproteincoupledreceptorgpcr
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