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-Arrestin-2-Deficient Mouse Models1
,¶
,¶
* Department of Veterans Affairs, Nashville, TN 37212; Departments of
Cancer Biology and
Plastic Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232;
Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707; and
¶ Department of Biochemistry, Meharry Medical College, Nashville, TN 37208
CXCR2 is a G-protein-coupled receptor (GPCR) that binds the CXC chemokines, CXCL1–3 and CXCL5–8, and induces intracellular signals associated with chemotaxis. Many adaptor proteins are actively involved in the sequestration, internalization, and trafficking of CXCR2 and transduction of agonist-induced intracellular signaling. We have previously shown that adaptor protein 
-arrestin-2 (arr2) plays a crucial role in transducing signals mediated through CXCR2. To further investigate the role of arr2 on CXCR2-mediated signaling during acute inflammation, zymosan-induced neutrophils were isolated from peritoneal cavities of arr2-deficient (arr2–/–) and their wild-type (arr2+/+) littermate mice, and neutrophil CXCR2 signaling activities were determined by measurement of Ca2+ mobilization, receptor internalization, GTPase activity, and superoxide anion production. The results showed that the deletion of arr2 resulted in increased Ca2+ mobilization, superoxide anion production, and GTPase activity in neutrophils, but decreased receptor internalization relative to wild-type mice. Two animal models, the dorsal air pouch model and the excisional wound healing model, were used to further study the in vivo effects of arr2 on CXCR2-mediated neutrophil chemotaxis and on cutaneous wound healing. Surprisingly, the recruitment of neutrophils was increased in response to CXCL1 in the air pouch model and in the excisional wound beds of arr2–/– mice. Wound re-epithelialization was also significantly faster in arr2–/– mice than in arr2+/+ mice. Taken together, the data indicate that arr2 is a negative regulator for CXCR2 in vivo signaling.
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