期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 98, 期 4, 页码 1601-1606出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.041608198
关键词
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资金
- NHLBI NIH HHS [R01 HL016037, HL16037] Funding Source: Medline
The two widely coexpressed isoforms of p-arrestin (termed beta -arrestin 1 and 2) are highly similar in amino acid sequence. The beta -arrestins bind phosphorylated heptahelical receptors to desensitize and target them to clathrin-coated pits for endocytosis, To better define differences in the roles of p-arrestin 1 and 2, we prepared mouse embryonic fibroblasts from knockout mice that lack one of the beta -arrestins (beta arr1-Ko and beta arr2-KO) or both (beta arr1/2-KO), as well as their wild-type (WT) littermate controls. These cells were analyzed for their ability to support desensitization and sequestration of the beta (2)-adrenergic receptor (beta (2)-AR) and the angiotensin II type 1A receptor (AT(1A)-R), Both beta arr1-KO and beta arr2-KO cells showed similar impairment in agonist-stimulated PI-AR and AT(1A)-R desensitization, when compared with their WT control cells, and the beta arr1/2-KO cells were even further impaired. Sequestration of the beta (2)-AR in the beta arr2-KO cells was compromised significantly (87% reduction), whereas in the beta arr1-KO cells it was not. Agonist-stimulated internalization of the AT(1A)-R was only slightly reduced in the beta arr1-KO but was unaffected in the beta arr2-KO cells. In the beta arr1/2-KO cells, the sequestration of both receptors was dramatically reduced. Comparison of the ability of the two beta -arrestins to sequester the beta (2)-AR revealed p-arrestin 2 to be 100-fold more potent than beta -arrestin 1 Down-regulation of the beta (2)-AR was also prevented in the beta arr1/2-KO cells, whereas no change was observed in the single knockout cells, These findings suggest that sequestration of various heptahelical receptors is regulated differently by the two beta -arrestins, whereas both isoforms are capable of supporting receptor desensitization and down-regulation.
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