Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1530-5. doi: 10.1073/pnas.1205756110. Epub 2013 Jan 7.
G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current "canonical" model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor-G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (G(S))-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin-PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor-G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of G(S) activation and increases the steady-state levels of activated G(S), leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.
G 蛋白偶联受体（GPCRs）通过激活异三聚体 G 蛋白参与广泛存在的跨膜信号转导过程。在当前 GPCR 信号的“经典”模型中，抑制蛋白通过损害受体-G 蛋白偶联和促进受体内化来终止受体信号。然而，甲状旁腺素受体 1（PTHR），一种参与骨和矿物质代谢的必需 GPCR，并不遵循这种传统的脱敏范例。β-抑制蛋白延长了甲状旁腺素（PTH）触发的 G 蛋白（G(S)）介导的 cAMP 生成，这一过程与内体上抑制蛋白-PTHR 复合物的持续存在相关，并且被认为与延长的生理钙和磷酸盐反应有关。这对当前的抑制蛋白介导的受体-G 蛋白解偶联模型提出了一个不可避免的悖论。在这里，我们表明 PTHR 在响应 PTH 刺激时形成包括抑制蛋白和 Gβγ 二聚体的三元复合物，这反过来又导致 G(S)激活的加速速率，并增加激活的 G(S)的稳态水平，从而延长 cAMP 的生成。这项工作为 GPCR 信号的替代模型提供了机制基础，其中抑制蛋白有助于维持激动剂激素对受体的作用。
