Role of Receptor Dimerization in G Protein Activation

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DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to identify the molecular mechanisms by which G protein-coupled receptors transduce signals into cells. This information will be important for understanding fundamental aspects of cell signaling, development, and disease mechanisms. Insights into how this important receptor superfamily works as ligand-activated switches will aid in drug design and greatly impact medicine more than half of currently prescribed pharmaceuticals target G protein-coupled receptors. The potential for new therapies acting on these receptors is great; an estimated 3 percent of the human genome encodes G protein-coupled receptors. Despite their widespread importance, we do not understand how the receptors actually function as ligand-activated switches. Recent evidence demonstrates that G protein-coupled receptors, such as adrenergic and dopamine receptors, form homodimers; the 8 and K-opiate receptors have been shown to form heterodimers with novel pharmacology. Little is known about if the receptors interact via specific dimer interfaces or larger oligomeric structures, the physiologic significance of receptor dimerization/oligomerization, and if this is a general mechanism for other G protein-coupled receptors. To address these fundamental questions, this proposal employs a variety of techniques including genetic studies, fluorescence energy transfer, biochemical crosslinking, and computer modeling. These studies will be performed on the human complement factor 5 (C5a) receptor, a chemoattractant receptor that mediates neutrophil chemotaxis. This receptor functions well when expressed in yeast, making possible high-throughput structure/function studies on the C5a receptor. In parallel studies in mammalian cells, the information gained from the genetic studies wifl be used to ask specific questions regarding receptor activation mechanisms and if dimerization / oligomerization plays a role in receptor function. These studies should add to our understanding of the receptor activation mechanisms for G protein signaling.