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The AT_1A receptor "gain-of-function" mutant N111S/329 is both constitutively active and hyperreactive to angiotensin II

Département d'Endocrinologie, Institut Cochin; Institut National de la Santé et de la Recherche Médicale, U567; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104; and Faculté de Médecine René Descartes, Université Paris Descartes, Unité Mixte de Recherche et de Service 8104, Paris, France

Submitted 21 September 2005 ; accepted in final form 30 November 2005

The renin-angiotensin-aldosterone system (RAAS) is central to cardiovascular and renal physiology. However, there is no animal model in which the activation of the RAAS only reflects the activation of the angiotensin II (ANG II) AT₁ receptor. As a first step to developing such a model, we characterized a gain-of-function mutant of the mouse AT_1A receptor. This mutant carries two mutations: N111S predicted to activate the receptor constitutively and a COOH-terminal deletion, 329, expected to reduce receptor internalization and desensitization. We expressed this double mutant (AT_1A-N111S/329) in heterologous cells. It showed a pharmacological profile consistent with that of other constitutively active mutants. Furthermore, it increased basal production of inositol phosphates, as well as basal cytosolic and nuclear ERK activities. Basal proliferation of cells expressing the mutant was also greater than that of the wild type. The double mutant was poorly internalized and failed to recruit -arrestin 2 in the presence of ANG II. It also showed hypersensitive and hyperreactive responses to ANG II for both inositol phosphate production and ERK activation. The additivity of the phenotypes of the two mutations makes this mutant an appropriate candidate to test the physiological consequences of the AT_1A receptor activation itself in transgenic animal models.

G protein-coupled receptor; hyperreactivity; -arrestin; extracellular signal-regulated kinase

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