The human angiotensin AT₁ receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation

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• 作者：Jakob Lerche Hansen ; Mark Aplin ; Jonas Tind Hansen ; Gitte Lund Christensen ; Marie Mi Bonde ; Mikael Schneider ; Stig Haunsø ; Hans H. Schiffer ; Ethan S. Burstein ; David M. Weiner ; Sø ; ren P. Shei
• 关键词：GPCR ; 7TM receptor ; Differential activation ; Angiotensin ; Arrestin ; AT₁ receptor
• 刊名：European Journal of Pharmacology
• 出版年：2008
• 出版时间：20 August 2008
• 年：2008
• 卷：590
• 期：1-3
• 页码：255-263
• 全文大小：856 K

文摘

The angiotensin AT₁ receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin AT₁ receptor signalling is illustrated by the common use of angiotensin AT₁ receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT₁ receptor can selectively signal through G protein-dependent and -independent mechanisms in recombinant expression systems, primary cells and in vivo. The in vivo work clearly demonstrates profoundly different cellular consequences of angiotensin AT₁ receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of angiotensin AT₁ receptor actions. However, it is currently unknown whether the human angiotensin AT₁ receptor can signal through G protein-independent mechanisms — and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT₁ receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT₁ receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the human angiotensin AT₁ receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes.