One of the most investigated areas of biology is the regulation of cellular function by binding of ligands to receptors on the extracellular surface of cells. Understanding how these receptors signal ligand binding to the interior of the cell -- signal transduction -- is key to understanding the establishment and regulation of homeostasis throughout the body. Additionally, pharmacological intervention in disease processes can be achieved by interfering with the ligand/receptor interaction, and so any additional understanding of the mechanisms whereby receptors transduce their signals has obvious importance in discovery and refinement of pharmacotherapies. This proposal specifically targets signal transduction of the human FSH receptor, which is an important hormonal response pathway in the regulation of fertility.
Four specific aims are enumerated: (1) determine the role of three intracellular loops and C- terminal tail of the FSH receptor in G protein coupling, (2) determine the role of specific amino acid residues present in each intracellular loop and in a segment from the membrane-proximal portion of the C-terminal tail of the FSH receptor, (3) quantify the turnover of G proteins involved in signal transduction triggered by activation of the FSH receptor, and (4) determine the role of down-regulation of G proteins coupled to the FSH receptor the cellular responses to different molecular forms of human FSH.
