title: Role of beta-arrestin-mediated desensitization and signaling in the control of angiotensin AT1a receptor-stimulated transcription.
abstract: 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.MEK.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.
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Lee
authors.forename: Hesham M
authors.initials: HM
authors.lastname: El-Shewy
authors.forename: Deirdre K
authors.initials: DK
authors.lastname: Luttrell
authors.forename: Louis M
authors.initials: LM
authors.lastname: Luttrell
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D000071557:beta-Arrestins; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D019390:Arrestins; D020033:Protein Isoforms; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000071557:beta-Arrestins; D000804:Angiotensin II; D048490:raf Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11