Research Initiation Award Grant for Identifying changes in serotonin receptor function due to naturally occurring single nucleotide polymorphisms (SNPs)

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The goal of this project at Fisk University is to identify novel signaling pathways that may be used by the serotonin (5-hydroxytryptamine; 5-HT) receptor which are revealed by examining subtly modified receptor structures, such as those encoded by single nucleotide polymorphisms (SNPs) found in human individuals. The objectives of the proposed research are to introduce into heterologous cells cDNAs encoding natural occurring polymorphic 5-HT2CRs whose sequence modifications are in regions previously identified as critical for coupling to G protein-mediated signaling pathways, and to characterize the functional consequences of these SNP-encoded sequence modifications. At least two undergraduate students per year will be involved in the research. Furthermore, master?s students in the lab will serve as role models for the undergraduates.The project will study the functional consequences of single nucleotide polymorphisms (SNPs) in the serotonin (5-HT) 2C receptor. 5-HT is a neurotransmitter that modulates a variety of neurophysiological responses by binding to one of 14 different receptor subtypes, one of which is the 5-HT2C receptor (5-HT2CR). The 5-HT2CR is a seven-transmembrane (7TM) spanning, G protein-coupled receptor (GPCR) that is involved in neuronal excitability, spatial learning, and appetite. Recent studies reveal that GPCRs may be a misnomer since many 7TM Receptors also activate cellular processes via non-G protein-coupled responses, primarily via the protein arrestin. The relative contribution of G Protein versus arrestin-mediated signaling is not well understood for the 5-HT2CR. SNPs identified in humans, which can lead to changes in protein sequence and, in some cases, altered activities, can provide insights into critical structure-function relationships of a protein. Though over 2,000 SNPs have been identified in the human 5-HT2CR, little characterization of structural and functional consequences of those SNPs has occurred, and no studies have explored whether or not such changes in receptor structure modify the preferential signaling via G protein-coupled versus arrestin-mediated pathways.