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β-Arrestins RegulateProtease-activatedReceptor-1Desensitization butNot Internalizationor Down-regulation May M. PaingAmy B. StuttsTrudy A. Kohout2002 год

β-Arrestins Regulate Protease-activated Receptor-1 Desensitization but Not Internalization or Down-regulation
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Аннотация: The widely expressed β-arrestin isoforms 1 and 2 bind phosphorylated G protein-coupled receptors (GPCRs) and mediate desensitization and internalization. Phosphorylation of protease-activated receptor-1 (PAR1), a GPCR for thrombin, is important for desensitization and internalization, however, the role of β-arrestins in signaling and trafficking of PAR1 remains unknown. To assess β-arrestin function we examined signaling and trafficking of PAR1 in mouse embryonic fibroblasts (MEFs) derived from β-arrestin (βarr) knockouts. Desensitization of PAR1 signaling was markedly impaired in MEFs lacking both βarr1 and βarr2 isoforms compared with wild-type cells. Strikingly, in cells lacking only βarr1 PAR1 desensitization was also significantly impaired compared with βarr2-lacking or wild-type cells. In wild-type MEFs, activated PAR1 was internalized through a dynamin- and clathrin-dependent pathway and degraded. Surprisingly, in cells lacking both βarr1 and βarr2 activated PAR1 was similarly internalized through a dynamin- and clathrin-dependent pathway and degraded, whereas the β2-adrenergic receptor (β2-AR) failed to internalize. A PAR1 cytoplasmic tail mutant defective in agonist-induced phosphorylation failed to internalize in both wild-type and β-arrestin knockout cells. Thus, PAR1 appears to utilize a distinct phosphorylation-dependent but β-arrestin-independent pathway for internalization through clathrin-coated pits. Together, these findings strongly suggest that the individual β-arrestin isoforms can differentially regulate GPCR desensitization and further reveal a novel mechanism by which GPCRs can internalize through a dynamin- and clathrin-dependent pathway that is independent of arrestins.
Год издания: 2002
Авторы: May M. Paing, Amy B. Stutts, Trudy A. Kohout, Robert J. Lefkowitz, JoAnn Trejo
Издательство: Elsevier BV
Источник: Journal of Biological Chemistry
Ключевые слова: Receptor Mechanisms and Signaling, Neuropeptides and Animal Physiology, Renin-Angiotensin System Studies
Другие ссылки: Journal of Biological Chemistry (PDF)
Journal of Biological Chemistry (HTML)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (HTML)
PubMed (HTML)