The long term goal of our studies is to gain insight into mechanisms mediating the effects of alcohol. Alcoholism is a chronic disorder that afflicts at least 1 million Americans and exacts a cost of over 166 million dollars per year (NIAAA data) in alcohol-related expenses. Despite its prevalence and cost to society, the molecular mechanisms underlying the actions of ethanol have not been fully elucidated. Recent studies suggest that ethanol produces many of its acute and chronic effects in the CNS through the 5HT3 and GABA-A ligand-gated neurotransmifter receptors. Although each of these receptors alone can mediate some of the actions of ethanol, both receptors are expressed in some neuronal populations. The possibility that cross-talk between these receptors mediates some of the actions of ethanol has not yet been studied. Although much is known about the GABAA receptor and its responses to ethanol, little is known about the 5-HT3 receptor or how it modulates the actions of ethanol. To investigate the importance of 5HT3 receptors in mediating the actions of ethanol, information concerning its subunit composition, distribution, function, and interactions is essential. To determine receptor subunit composition and function, studies will be performed on transfected cells expressing the 5HT3A subunit in the presence and absence of the newly discovered 5HT36 subunit. These studies will determine whether subunit coexpression alters receptor properties and will provide insight into the role of the B subunit. Next, the possibility that the 5HT3 receptor subunits can interact with GABA-A receptor subunits in transfected cells will be determined. Finally, since the hippocampus is involved in mediating the cognitive effects of alcohol, and 5HT3 and GABA-A receptors are coexpressed in this region, studies will be performed to characterize receptor subunit distribution, colocalization and interactions in hippocampal neurons in culture. Together, these studies will provide novel information concerning 5HT3 receptor composition and will provide tools for future research to elucidate its function in mediating the actions of alcohol.
|Quirk, Phillip L; Siegel, Ruth E (2005) The serotonin type 3A receptor facilitates luteinizing hormone release and LHbeta promoter activity in immortalized pituitary gonadotropes. Endocrine 27:37-43|
|Quirk, Phillip L; Rao, Suma; Roth, Bryan L et al. (2004) Three putative N-glycosylation sites within the murine 5-HT3A receptor sequence affect plasma membrane targeting, ligand binding, and calcium influx in heterologous mammalian cells. J Neurosci Res 77:498-506|