Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 4, Pages 2088-2097Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M706892200
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- NIDDK NIH HHS [DK55524] Funding Source: Medline
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Heptahelical G protein-coupled receptors employ several mechanisms to activate the ERK1/2 cascade and control gene transcription. Previous work with the angiotensin AT1a receptor has shown that G(q/11) activation leads to a rapid and transient rise in ERK1/2 activity, whereas beta-arrestin binding supports sustained ERK1/2 activation by scaffolding a Raf center dot MEK center dot ERK complex associated with the internalized receptor. In this study, we compared the role of the two beta-arrestin isoforms in AT1a receptor desensitization, ERK1/2 activation and transcription using selective RNA interference. In HEK293 cells, both the native AT1a receptor and a G protein-coupling deficient DRY/AAY mutant recruited beta-arrestin1 and beta-arrestin2 upon angiotensin binding and internalized with the receptor. In contrast, only beta-arrestin2 supported protein kinase C-independent ERK1/2 activation by both the AT1a and DRY/AAY receptors. Using focused gene expression filter arrays to screen for endogenous transcriptional responses, we found that silencing beta-arrestin1 or beta-arrestin2 individually did not alter the response pattern but that silencing both caused a marked increase in the number of transcripts that were significantly up-regulated in response to AT1a receptor activation. The DRY/AAY receptor failed to elicit any detectable transcriptional response despite its ability to stimulate beta-arrestin2- dependent ERK1/2 activation. These results indicate that the transcriptional response to AT1a receptor activation primarily reflects heterotrimeric G protein activation. Although beta-arrestin1 and beta-arrestin2 are functionally specialized with respect to supporting G protein-independent ERK1/2 activation, their common effect is to dampen the transcriptional response by promoting receptor desensitization.
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