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RECEPTORS AND SIGNAL TRANSDUCTION

Differential effects of -arrestins on the internalization, desensitization and ERK1/2 activation downstream of protease activated receptor-2

¹Division of Biomedical Sciences, ²Biochemistry and Molecular Biology Program, ³Cell, Molecular and Developmental Biology Program, University of California, Riverside, Riverside, California

Submitted 6 January 2007 ; accepted in final form 14 April 2007

-Arrestins-1 and 2 are known to play important roles in desensitization of membrane receptors and facilitation of signal transduction pathways. It has been previously shown that -arrestins are required for signal termination, internalization, and ERK1/2 activation downstream of protease-activated-receptor-2 (PAR-2), but it is unclear whether they are functionally redundant or mediate specific events. Here, we demonstrate that in mouse embryonic fibroblasts (MEFs) from -arrestin-1/2 knockout mice, Gq signaling by PAR-2, as measured by mobilization of intracellular Ca²⁺, is prolonged. Only expression of -arrestin-1 shortened the signal duration, whereas either -arrestin-1 or 2 was able to restore PKC-induced receptor desensitization. -arrestin-1 also mediated early, while -arrestin-2 mediated delayed, receptor internalization and membrane-associated ERK1/2 activation. While -arrestin-1 colocalized with a lysosomal marker (LAMP-1), -arrestin-2 did not, suggesting a specific role for -arrestin-1 in lysosomal receptor degradation. Together, these data suggest distinct temporal and functional roles for -arrestins in PAR-2 signaling, desensitization, and internalization.

arrestins; PAR-2; protease-activated-receptor; G protein-coupled receptor; ERK1/2

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