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

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