The proposal of this RCDA application is to study the structure-function relationship of the serotonin 1c receptor from the mouse brain. As a neurotransmitter, serotonin exerts diverse effects in the central nervous system and in periphery by interacting with specific membrane receptors. These receptors are also the targets of a number of clinically important drugs as well as several hallucinogenic compounds. The goal of this proposal is to use the cloned serotonin 1c receptor CDNA for functional expression of the receptor in Xenopus oocytes and in mammalian cell culture. This receptor is chosen for study because two unusual aspects: 1) The receptor contains wight hydrophobic domains, unlike other G protein- coupled receptors that have seven. Preliminary studies suggest that this additional domain may serve a functional role in ligand binding; 2) Cells expressing the receptor respond to changes in external calcium in a manner similar to serotonin-induced effect, and this takes place only after pretreatment with serotonin. This therefore suggests a novel mechanism for receptor-mediated transmembrane signaling. Detailed molecular analysis will be carried out by generating specific mutations in the receptor, and electrophysiological and pharmacological methods will be used to characterize functional modifications.
The aim of this proposal relates to the candidate's long-term goal: to develop a research career in the field of neurobiology by using the expertise in molecular biology and electrophysiology to study fundamental questions in neurobiology. The award would permit he candidate to devote blocks of uninterrupted time to further his knowledge in areas important to his career goal: auditing classes in neurobiology and acquiring hands-on experience in serotonin receptor pharmacology.
