Role of beta-arrestin-dependent chemotaxis in protease-activated-receptor-2-induc

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DESCRIPTION (provided by applicant): Protease-activated-receptor-2 (PAR-2) is a G-protein-coupled-receptor (GPCR) activated by a number of trypsin-like proteases, many of which are found at sites of inflammation or may be released by invading pathogens(5; 7). Current studies indicate that PAR-2 may have both protective and pathogenic effects in inflammatory diseases such as asthma and colitis, depending on the disease model, the administration of PAR-2 agonist and the physiological read-out (1-4; 8; 11; 14-16). Our laboratory has demonstrated multiple G-protein-independent effects of PAR-2, that are mediated by a family of proteins called 2-arrestins (6; 9; 10; 13; 17; 18). 2-arrestins effectively 'steal' signaling molecules from the G-protein pathway, some of which they directly inhibit others of which are activated only in specific cellular microdomains. Additionally, 2-arrestins can recruit and activate molecules not affected by G-protein coupling (17; 18). This 2-arrestin-dependent PAR2 signaling mechanism allows one receptor to orchestrate different physiological events in a cell-type specific manner. Recently, there has been a substantial amount of interest in PAR-2 as a therapeutic target for asthma and other inflammatory disorders (4; 12); however, while some groups propose agonists others propose antagonists of PAR2 as therapeutics. This grant tests the novel hypothesis that 2-arrestin-dependent and G-protein-dependent signals may dominate in different cell types leading to some inflammatory and some protective responses, by assessing PAR2 evoked asthma in mice lacking either of the two 2-arrestins (knockout mice), and by transplanting bone marrow of PAR-2 knockout mice into wild type. Elucidation of the specific role of each signaling pathway in inflammation could lead to the development of pathway specific PAR2 agonists and/or antagonists. Public Health Relevance: Currently Protease-activated-receptor-2 (PAR2) is being considered as a target for treatment of asthma, colitis and cancer; however, there exists considerable controversy over its actual role in inflammation. Some groups are proposing aerosolized activators as a treatment for asthma, while others propose antagonizing it to achieve suppression of inflammation. This proposal aims to dissect the pathways leading to pro and anti-inflammatory effects of PAR-2 in the airways, with the hope that this may lead to the eventual development of pathway-specific drugs.