Arrestins regulate numerous G protein-coupled receptors (GPCRs) by disrupting GPCR-G protein interaction and "arresting" the ability of receptors to signal. Although considerable evidence of the importance of arrestins has come from studies employing cellular overexpression systems, our understanding of arrestin regulation of endogenous GPCRs in physiological systems is limited. We propose to characterize the capacity and selectivity of arrestins for regulating GPCRs in airway smooth muscle (ASM), with the ultimate goal of targeting arrestins as a means of improving the therapeutic efficacy of inhaled beta-agonists in the treatment of asthma and COPD. Based on preliminary data presented herein, we hypothesize that differences in beta-arrestin-1 and beta-arrestin-2 selectivity for Gq- and Gs- coupled receptors can be exploited to enhance the ability of beta-agonists to relax ASM contracted by other GPCRs.
Aims 1 &2 will establish the selectivity of beta-arrestin-1 and beta-arrestin-2 for those GPCRs that either mediate contraction (including muscarinic, cysteinyl leukotriene, and histamine receptors) or relaxation (beta-2-adreneric and prostaglandin E2 receptors) of ASM.
Aim 1 will utilize molecular and genetic approaches to target beta-arrestin-1, beta-arrestin-2, or both in ASM cells and tissue derived from both humans and mice. Affects of arrestin inhibition or gene ablation on both ASM signaling and contractile properties by GPCRs will be assessed.
Aim 2 will perform complementary physiological measurements to determine the effect of arrestin gene ablation on the regulation of ASM contraction and relaxation in vivo. Collectively, these studies will provide a highly mechanistic analysis of arrestin selectivity in ASM and identify approaches for differentially regulating receptors that mediate contraction or relaxation of ASM.
These studies seek to identify the usefulness (as an asthma therapy) of inhibiting a key regulatory molecule in airway smooth muscle. Understanding how beta-arrestin-1 or beta-arrestin-2 regulate receptors in smooth muscle may allow us to improve the ability of drugs to relax smooth muscle while at the same time inhibiting the stimuli that cause airway constriction and wheezing.
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