Translating in vitro ligand bias into in vivo efficacy.
Translating in vitro ligand bias into in vivo efficacy.
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DOI：
10.1016/j.cellsig.2017.05.002
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发表时间：
2018-01
影响因子：
4.8
通讯作者：
Gesty-Palmer D
中科院分区：
文献类型：
--
作者：
Luttrell LM;Maudsley S;Gesty-Palmer D
越来越明显的是，配体结构影响G蛋白偶联受体（GPCR）与其下游效应子接合的效率和它们被激活的方式。因此，“偏向”激动剂，其内在功效不同于天然配体的合成配体，提供了一种以促进有益信号同时阻断潜在有害信号的方式操纵GPCR信号传导的策略。尽管如此，在将体外配体功效（其通常在异源表达系统中测量）与体内生物反应相关联方面存在重大挑战，其中配体作用于天然表达的受体并且存在内源性配体。这对于抑制蛋白途径选择性“偏向性”激动剂尤其如此。1型甲状旁腺激素受体（PTH 1 R）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，成骨细胞系细胞上表达的PTH 1 R是骨质疏松症的既定治疗靶点。在体外，PTH 1 R信号传导对配体结构高度敏感，并且已经鉴定了影响G蛋白偶联的选择性/动力学或参与抑制蛋白依赖性信号传导机制而不激活异源三聚体G蛋白的PTH类似物。在体内，常规PTH类似物的间歇给药加速成骨细胞骨形成的速率，主要通过已知的cAMP依赖性机制。奇怪的是，间歇和连续施用抑制蛋白途径选择性PTH类似物（其在体内预期拮抗内源性PTH 1 R-cAMP信号传导）也增加骨量。从治疗动物的组织的转录组学分析表明，常规和抑制蛋白途径选择性PTH 1 R配体的行为在很大程度上不同的方式，后者主要影响参与细胞周期，生存和迁移/细胞骨架动力学的调节途径。这种多维的体外和体内配体偏好分析可以提供对体内非经典抑制蛋白介导的信号传导途径的生理作用的见解，并提供将抑制蛋白途径选择性配体转化为可行的治疗剂的概念框架。
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 (PTH1R) is a case in point. Parathyroid hormone (PTH) is the principal physiological regulator of calcium homeostasis, and PTH1R expressed on cells of the osteoblast lineage are an established therapeutic target in osteoporosis. In vitro, PTH1R 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 PTH1R-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.
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影响因子：
4.8
作者：
Bisello, A;Chorev, M;Ferrari, SL
通讯作者：
Ferrari, SL
影响因子：
6.2
作者：
Bouxsein, ML;Pierroz, DD;Ferrari, SL
通讯作者：
Ferrari, SL
影响因子：
4.8
作者：
Friedman, PA;Gesek, FA;Willick, GE
通讯作者：
Willick, GE
DOI：
10.1124/jpet.105.090886
发表时间：
2005-11-01
影响因子：
3.5
作者：
Ehlert, FJ
通讯作者：
Ehlert, FJ
影响因子：
14.8
作者：
Ferrandon, Sebastien;Feinstein, Timothy N.;Castro, Marian;Wang, Bin;Bouley, Richard;Potts, John T.;Gardella, Thomas J.;Vilardaga, Jean-Pierre
通讯作者：
Vilardaga, Jean-Pierre