Division of Endocrinology, Diabetes & Medical Genetics, Medical University of South Carolina, Charleston, SC 29425, USA; Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, 29401, USA.
Translational Neurobiology Group, VIB Department of Molecular Genetics, Laboratory of Neurogenetics-Institute Born-Bunge, University of Antwerp, Belgium.
Cell Signal. 2018 Jan;41:46-55. doi: 10.1016/j.cellsig.2017.05.002. Epub 2017 May 7.
It is increasingly apparent that ligand structure influences both the efficiency with which G protein-coupled receptors (GPCRs) engage their downstream effectors and the manner in which they are activated. Thus, 'biased' agonists, synthetic ligands whose intrinsic efficacy differs from the native ligand, afford a strategy for manipulating GPCR signaling in ways that promote beneficial signals while blocking potentially deleterious ones. Still, there are significant challenges in relating in vitro ligand efficacy, which is typically measured in heterologous expression systems, to the biological response in vivo, where the ligand is acting on natively expressed receptors and in the presence of the endogenous ligand. This is particularly true of arrestin pathway-selective 'biased' agonists. The type 1 parathyroid hormone receptor (PTHR) is a case in point. Parathyroid hormone (PTH) is the principal physiological regulator of calcium homeostasis, and PTHR expressed on cells of the osteoblast lineage are an established therapeutic target in osteoporosis. In vitro, PTHR signaling is highly sensitive to ligand structure, and PTH analogs that affect the selectivity/kinetics of G protein coupling or that engage arrestin-dependent signaling mechanisms without activating heterotrimeric G proteins have been identified. In vivo, intermittent administration of conventional PTH analogs accelerates the rate of osteoblastic bone formation, largely through known cAMP-dependent mechanisms. Paradoxically, both intermittent and continuous administration of an arrestin pathway-selective PTH analog, which in vivo would be expected to antagonize endogenous PTHR-cAMP signaling, also increases bone mass. Transcriptomic analysis of tissue from treated animals suggests that conventional and arrestin pathway-selective PTH1R ligands act in largely different ways, with the latter principally affecting pathways involved in the regulation of cell cycle, survival, and migration/cytoskeletal dynamics. Such multi-dimensional in vitro and in vivo analyses of ligand bias may provide insights into the physiological roles of non-canonical arrestin-mediated signaling pathways in vivo, and provide a conceptual framework for translating arrestin pathway-selective ligands into viable therapeutics.
越来越明显的是，配体结构会影响 G 蛋白偶联受体（GPCR）与其下游效应器结合的效率，以及它们被激活的方式。因此，“偏向性”激动剂，即内在效力不同于天然配体的合成配体，为操纵 GPCR 信号提供了一种策略，可以促进有益信号，同时阻断潜在的有害信号。然而，将体外配体效力与体内生物学反应相关联仍然存在重大挑战，因为在体内，配体作用于天然表达的受体，并存在内源性配体。这在具有选择性的抑制 G 蛋白偶联的“偏向性”激动剂中尤其如此。甲状旁腺激素受体 1 型（PTHR1）就是一个很好的例子。甲状旁腺激素（PTH）是钙稳态的主要生理调节剂，成骨细胞谱系细胞上表达的 PTHR1 是骨质疏松症的既定治疗靶点。在体外，PTHR1 信号对配体结构高度敏感，已经确定了影响 G 蛋白偶联选择性/动力学的 PTH 类似物，或通过不激活异三聚体 G 蛋白而参与衔接蛋白依赖性信号机制的 PTH 类似物。在体内，常规 PTH 类似物的间歇性给药会加速成骨细胞的骨形成速度，主要通过已知的 cAMP 依赖性机制。矛盾的是，间歇性和连续性给药的一种选择性抑制 G 蛋白偶联的 PTH 类似物也会增加骨量，而这种类似物在体内预计会拮抗内源性 PTHR1-cAMP 信号。对治疗动物组织的转录组分析表明，常规和选择性抑制 G 蛋白偶联的 PTH1R 配体作用方式基本不同，后者主要影响细胞周期、存活和迁移/细胞骨架动力学调节的途径。这种体外和体内配体偏向的多维分析可能会深入了解非典型衔接蛋白介导的信号通路在体内的生理作用，并为将选择性抑制 G 蛋白偶联的配体转化为可行的治疗药物提供概念框架。
