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Dominant-negative AT2 receptor oligomers induce G-protein arrest and symptoms of neurodegeneration


AbdAlla, S; Lother, H; El Missiry, A; Sergeev, P; Langer, A; El Faramawy, Y; Quitterer, U (2009). Dominant-negative AT2 receptor oligomers induce G-protein arrest and symptoms of neurodegeneration. Journal of Biological Chemistry, 284(10):6566-6574.

Abstract

Neurodegeneration in Alzheimer;s disease (AD) correlates with dysfunction of signaling mediated by Gaq/11. Non-dissociable angiotensin II AT2 receptor oligomers are linked to the impaired Gaq/11-stimulated signaling of AD patients and transgenic mice with AD-like symptoms. To further analyze the role of AT2 receptor oligomers, we induced the formation AT2 oligomers in an in vitro cell system. Similarly as in vivo, sequential oxidative and transglutaminase-dependent cross-linking steps triggered the formation of AT2 oligomers in vitro. Elevated reactive oxygen species mediated oxidative cross-linking of AT2 monomers to dimers involving tyrosine residues located at putative inter-receptor contact sites of the cytoplasmic loop connecting transmembrane helices III/IV. Cross-linked AT2 dimers were subsequently a substrate of activated transglutaminase-2, which targeted the carboxyl terminus of AT2 dimers as assessed by truncated and chimeric AT2 receptors, respectively. AT2 oligomers acted as dominant-negative receptors in vitro by mediating Gaq/11 protein sequestration and Gaq/11 protein arrest. The formation of AT2 oligomers and G-protein dysfunction could be suppressed in vitro and in vivo by an AT2 receptor mutant. Inhibition of AT2 oligomerization upon stereotactic expression of the AT2 receptor mutant revealed that Gaq/11-sequestering AT2 oligomers enhanced the development of neurodegenerative symptoms in the hippocampus of transgenic mice with AD-like pathology. Thus, AT2 oligomers inducing Gaq/11 arrest are causally involved in inducing symptoms of neurodegeneration.

Abstract

Neurodegeneration in Alzheimer;s disease (AD) correlates with dysfunction of signaling mediated by Gaq/11. Non-dissociable angiotensin II AT2 receptor oligomers are linked to the impaired Gaq/11-stimulated signaling of AD patients and transgenic mice with AD-like symptoms. To further analyze the role of AT2 receptor oligomers, we induced the formation AT2 oligomers in an in vitro cell system. Similarly as in vivo, sequential oxidative and transglutaminase-dependent cross-linking steps triggered the formation of AT2 oligomers in vitro. Elevated reactive oxygen species mediated oxidative cross-linking of AT2 monomers to dimers involving tyrosine residues located at putative inter-receptor contact sites of the cytoplasmic loop connecting transmembrane helices III/IV. Cross-linked AT2 dimers were subsequently a substrate of activated transglutaminase-2, which targeted the carboxyl terminus of AT2 dimers as assessed by truncated and chimeric AT2 receptors, respectively. AT2 oligomers acted as dominant-negative receptors in vitro by mediating Gaq/11 protein sequestration and Gaq/11 protein arrest. The formation of AT2 oligomers and G-protein dysfunction could be suppressed in vitro and in vivo by an AT2 receptor mutant. Inhibition of AT2 oligomerization upon stereotactic expression of the AT2 receptor mutant revealed that Gaq/11-sequestering AT2 oligomers enhanced the development of neurodegenerative symptoms in the hippocampus of transgenic mice with AD-like pathology. Thus, AT2 oligomers inducing Gaq/11 arrest are causally involved in inducing symptoms of neurodegeneration.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:6 March 2009
Deposited On:08 Jan 2009 09:47
Last Modified:05 Apr 2016 12:45
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Additional Information:This research was originally published in Abdalla, S; Lother, H; El Missiry, A; Sergeev, P; Langer, A; El Faramawy, Y; Quitterer, U (2009). Dominant-negative AT2 receptor oligomers induce G-protein arrest and symptoms of neurodegeneration. Journal of Biological Chemistry, 284(10):6566-6574. © the American Society for Biochemistry and Molecular Biology
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/jbc.M808277200
PubMed ID:19074439

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