Aplin Mark, Bonde Marie Mi, Hansen Jakob Lerche
Laboratory for Molecular Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
J Mol Cell Cardiol. 2009 Jan;46(1):15-24. doi: 10.1016/j.yjmcc.2008.09.123. Epub 2008 Sep 26.
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.
血管紧张素AT(1)受体是治疗心血管疾病（如高血压、糖尿病肾病、心脏肥大、心律失常和心力衰竭）的重要药理学靶点。同时，AT(1)受体已成为一个突出的模型，用于阐释受体可能具有多种活性状态并产生不同功能结果这一新兴概念。AT(1)受体采用两种主要信号通路，即1) 经典的G(q)蛋白依赖性激活肌醇磷酸周转和细胞内钙释放，以及2) G蛋白非依赖性募集β-抑制蛋白支架信号复合物，后者激活蛋白激酶通路。在AT(1)受体的突变研究以及用血管紧张素II类似物进行的药理学探究中，已证实受体激活的不同状态对个别下游通路具有偏好性（功能选择性）。这些研究还提供了有关导致不同功能结果的构象变化的线索。在本综述中，我们评估了目前关于AT(1)受体激活分子决定因素的知识，这些因素可能区分G蛋白依赖性和非依赖性行为。虽然已知G蛋白激活具有有害作用，但AT(1)受体的G蛋白非依赖性信号传导与细胞存活和更新、心脏收缩调节及细胞迁移等表型有关。因此，目前推测选择性阻断G蛋白作用并同时激活G蛋白非依赖性信号传导将被证明是改善心血管治疗的可行策略。受体（如AT(1)受体）功能选择性的药理学观点促使人们阐明控制不同信号事件的分子机制。
