期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 46, 期 1, 页码 15-24出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2008.09.123
关键词
GPCR; 7TM; Receptor; AT(1); Angiotensin; Functional selectivity; Biased agonism; Molecular mechanisms; Cardiovascular physiology and pharmacology; Structure/activity
资金
- Danish Medical Research Council
- Kobmand i Odense Johan og Hanne Weimann f. Seedorffs legat
- Danish National Research Foundation
- Danish Heart Foundation [07-4-B635-A1386-22361]
- Novo Nordisk Foundation
The angiotensin AT(1) receptor is an important pharmacological target in the treatment of cardiovascular disorders, such as hypertension, diabetic nephropathy, cardiac hypertrophy, arrhythmia and failure. Simultaneously, the AT(1) receptor has emerged to be a prominent model for the emerging concept that receptors may attain multiple active states with differentiated functional outcomes. Two major signalling pathways are employed by the AT(1) receptor, namely 1) the canonical G(q) protein-dependent activation of inositol phosphate turnover and intracellular calcium release, and 2) G protein-independent recruitment of beta-arrestin-scaffolded signalling complexes that activate protein kinase pathways. Different states of receptor activation with preference for individual downstream pathways (functional selectivity) have been demonstrated in mutational studies of the AT(1) receptor and by pharmacological probing with analogues of angiotensin II. These studies also provide clues about the conformational changes that underlie different functional outcomes. In this review, we evaluate current knowledge of the molecular determinants of AT(1) receptor activation, which may distinguish G protein-dependent and -independent behaviour. While G protein activation is known to be detrimental, G protein-independent signalling by the AT(1) receptor has been associated with phenotypes such as cell survival and renewal, regulation of cardiac contraction and cell migration. It is therefore currently hypothesized that selective blockade of G protein actions and simultaneous activation of G protein-independent signalling will prove to be a feasible strategy for improved cardiovascular therapy. The pharmacological perspectives of functional selectivity by receptors, such as the AT(1) receptor, urge the elucidation of molecular mechanisms that govern disparate signalling events. (C) 2008 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据