The broad goal of this proposal is to understand the functional consequences of a single nucleotide polymorphism in the human 5-HT2C receptor and examine if it plays a role in depression. This will be accomplished by using pharmacology to study the signal transduction of polymorphic receptors.
The specific aims of this research proposal are to: (1) Generate and express edited and non-edited polymorphic receptors stably using PCR site-directed mutagenesis. (2) Examine the functional impact of the SNP on the 5-HT2C receptor by performing radioligand binding to compare affinities for different drugs, phosphoinositide hydrolysis to examine potency values, calcium imaging to measure calcium dynamics, immunocytochemistry and surface biotinylation to study the cellular distribution of the receptors. (3) Elucidate the association of the cys23ser SNP and subpopulations of depressed patients, and screen these depressed patients and African patient samples for novel polymorphisms. This project will give us further insight into the complexity of depression and how genetic diversity in combination with molecular diversity can lead to functional consequences and eventually symptoms of a disease.
| Hahn, M K; Blackford, J U; Haman, K et al. (2008) Multivariate permutation analysis associates multiple polymorphisms with subphenotypes of major depression. Genes Brain Behav 7:487-95 |
| Fentress, H M; Grinde, E; Mazurkiewicz, J E et al. (2005) Pharmacological properties of the Cys23Ser single nucleotide polymorphism in human 5-HT2C receptor isoforms. Pharmacogenomics J 5:244-54 |
