Arrestins were originally discovered as negative regulators of G protein-coupled receptor (GPCR) signaling via G proteins. Recent discoveries show that the arrestin-receptor complex initiates signaling through distinct G protein-independent pathways, including those that regulate cell death, survival, and proliferation via MAP kinases. Faulty regulation of GPCR signaling induced by mutations or environmental insults underlies many human diseases. Unfortunately, therapeutic targeting receptor signaling via arrestins, which are natural GPCR regulators, is hampered by lack of selectivity of the non- visual subtypes, both of which interact with dozens of GPCRs. Here we propose to construct and functionally characterize non-visual arrestins with dramatically enhanced specificity for individual GPCRs. Receptor-specific mutants, as well as their enhanced phosphorylation-independent variants, will be tested for their ability to selectively regulate signaling by particuar GPCR subtypes via G proteins, arrestins, and receptor trafficking. Mutants that preferentially interact with particular receptors will be tested for their ability to selectively disrupt receptor coupling to cognate G proteins. Mutants with high preference for D1 and D2 dopamine receptors will be used to determine which receptor subtype plays key role in the development of dyskinesia, the most common devastating side effect of current anti- parkinsonian therapy. Receptor-specific regulation of GPCR signaling has therapeutic potential in multiple disorders associated with congenital or acquired imbalances in cell signaling.
This proposal focuses on the construction and functional characterization of non-visual arrestins with dramatically enhanced specificity for individual G protein-coupled receptors (GPCRs). Receptor-specific mutants will be tested for their ability to selectively regulate signaling by particular GPCR subtypes via G proteins and arrestins, and to determine dopamine receptor subtype that plays key role in dyskinesia, a common side effect of currently used treatment for Parkinson's disease. Receptor-specific regulation of GPCR signaling has therapeutic potential in multiple disorders associated with congenital or acquired imbalances in cell signaling.
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