G protein dependent signaling pathways regulate biological processes triggered by many hormones, inflammatory mediators, neurotransmitters and sensory stimuli, thereby coordinating a diverse array of cell, tissue and organ functions in the adult. These pathways also regulate embryonic development. Perturbations of G protein signaling pathways are associated with many human diseases, including cancer, heart failure, asthma and endocrine disorders. G protein signaling pathways are the targets of more than half of the drugs used today in clinical medicine. Therefore, basic research of G protein signaling pathways will continue to reveal novel disease mechanisms and fuel the discovery process for novel therapeutic agents used to treat a variety of human diseases. To reveal novel and fundamentally important mechanisms of G protein-coupled receptor (GPCR) signaling and regulation, this project uses yeast GPCRs as simple and experimentally tractable models that are broadly applicable throughout biology. The proposal builds on preliminary data showing that a yeast GPCR is dimeric or oligomeric in vivo, and that endocytic transport of this GPCR requires actin polymerization stimulated by a WASp homolog that activates the Arp2/3 complex.
Specific aims are to: 1) Determine whether GPCR biogenesis, signaling and/or endocytosis requires formation of receptor dimers and/or oligomers. 2) Determine whether heterooligomerization between two different GPCRs regulates receptor biogenesis, signaling or endocytosis. 3) Determine the mechanism by which a WASp homolog promotes actin polymerization-dependent transport of GPCR-bearing endosomes. Completion of this project will yield new concepts and mechanisms important for designing new therapeutics targeted to GPCRs and for understanding disease mechanisms caused by dysfunctional GPCR signaling.
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