Dominant Negative AT₂ Receptor Oligomers Induce G-protein Arrest and Symptoms of Neurodegeneration^*

Said AbdAlla, Heinz Lother, Ahmed el Missiry, Pavel Sergeev^¶, Andreas Langer^¶, Yasser el Faramawy, , and Ursula Quitterer^¶1

Heinrich-Pette-Institute, Martinistrasse 52, D-20251 Hamburg, Germany, the Medical Research Center, Ain Shams University Hospital, Cairo, Egypt, and the ^¶Department of Molecular Pharmacology, Swiss Federal Institute of Technology and University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland

Abstract: Neurodegeneration in Alzheimer's disease (AD) correlates with dysfunction of signaling mediated by G_q/11. Nondissociable angiotensin II AT₂ receptor oligomers are linked to the impaired G_q/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 of 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 interreceptor 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 G_q/11 protein sequestration and G_q/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 G_q/11-sequestering AT₂ oligomers enhanced the development of neurodegenerative symptoms in the hippocampus of transgenic mice with AD-like pathology. Thus, AT₂ oligomers inducing G_q/11 arrest are causally involved in inducing symptoms of neurodegeneration.

Received for publication October 29, 2008. Revision received December 11, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Y17M70, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Fax: 41-44-635-6881; E-mail: ursula.quitterer{at}pharma.ethz.ch.

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