The AT1A receptor "gain-of-function" mutant N111S/Δ329 is both constitutively active and hyperreactive to angiotensin II

被引:12
作者
Billet, S
Bardin, S
Tacine, R
Clauser, E
Conchon, S
机构
[1] Fac Med Cochin, Dept Endocrinol, Inst Cochin, F-75014 Paris, France
[2] INSERM U567, Paris, France
[3] CNRS UMR 8104, Paris, France
[4] Univ Paris Descartes, Fac Med Rene Descartes, UMRS 8104, Paris, France
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2006年 / 290卷 / 05期
关键词
G protein-coupled receptor; hyperreactivity; beta-arrestin; extracellular signal-regulated kinase;
D O I
10.1152/ajpendo.00458.2005
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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) AT(1) 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, Delta 329, expected to reduce receptor internalization and desensitization. We expressed this double mutant (AT(1A)-N111S/Delta 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 beta-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.
引用
收藏
页码:E840 / E848
页数:9
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