Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Sci Transl Med. 2009 Oct 7;1(1):1ra1. doi: 10.1126/scitranslmed.3000071.
About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through beta-arrestins; so-called biased agonists can selectively activate these distinct pathways. Here, we investigate selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)-PTH-related protein receptor (PTH1R), (D-Trp(12),Tyr(34))-PTH(7-34) (PTH-betaarr), which activates beta-arrestin but not classic G protein signaling. In mice, PTH-betaarr induces anabolic bone formation, as does the nonselective agonist PTH(1-34), which activates both mechanisms. In beta-arrestin2-null mice, the increase in bone mineral density evoked by PTH(1-34) is attenuated and that stimulated by PTH-betaarr is ablated. The beta-arrestin2-dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. These results show that a biased agonist selective for the beta-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists. Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity.
目前大约有 40%的治疗药物是通过七次跨膜受体（7TMRs）发挥作用的。当这些受体被配体激活时，会触发两条独立向细胞传递信号的途径：一条通过异三聚体 GTP 结合蛋白（G 蛋白），另一条通过β-arrestin；所谓的偏激动剂可以选择性地激活这些不同的途径。在这里，我们通过使用偏激动剂来研究这些途径的选择性激活，该偏激动剂针对的是甲状旁腺激素（PTH）-甲状旁腺激素相关蛋白受体（PTH1R）的 1 型，（D-Trp(12),Tyr(34))-PTH(7-34)（PTH-betaarr），它激活β-arrestin 而不激活经典 G 蛋白信号。在小鼠中，PTH-betaarr 诱导合成代谢性骨形成，非选择性激动剂 PTH(1-34) 也是如此，它激活了这两种机制。在β-arrestin2 缺失的小鼠中，PTH(1-34) 引起的骨密度增加被减弱，而 PTH-betaarr 引起的增加则被消除。β-arrestin2 依赖性途径主要参与小梁骨形成，不会刺激骨吸收。这些结果表明，选择性激活β-arrestin 途径的偏激动剂可以在体内引起与非选择性激动剂不同的反应。具有这些特性的配体可能成为改善 7TMR 定向药理学药物的基础，从而提高治疗特异性。
