Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.
Nat Chem Biol. 2011 May;7(5):278-84. doi: 10.1038/nchembio.545. Epub 2011 Mar 27.
The generation of cAMP by G protein-coupled receptors (GPCRs) and its termination are currently thought to occur exclusively at the plasma membrane of cells. Under existing models of receptor regulation, this signal is primarily restricted by desensitization of the receptors through their binding to β-arrestins. However, this paradigm is not consistent with recent observations that the parathyroid hormone receptor type 1 (PTHR) continues to stimulate cAMP production even after receptor internalization, as β-arrestins are known to rapidly bind and internalize activated PTHR. Here we show that binding to β-arrestin1 prolongs rather than terminates the generation of cAMP by PTHR, and that cAMP generation correlates with the persistence of arrestin-receptor complexes on endosomes. PTHR signaling is instead turned off by the retromer complex, which regulates the movement of internalized receptor from endosomes to the Golgi apparatus. Thus, binding by the retromer complex regulates the sustained generation of cAMP triggered by an internalized GPCR.
目前认为，G 蛋白偶联受体（GPCR）产生 cAMP 及其终止仅发生在细胞的质膜上。在现有的受体调节模型中，这种信号主要通过受体与β-arrestins 的结合而被脱敏所限制。然而，这一范例与最近的观察结果不一致，即甲状旁腺激素受体 1 型（PTHR）在受体内化后仍继续刺激 cAMP 的产生，因为众所周知，β-arrestins 会迅速结合并内化激活的 PTHR。在这里，我们表明，与β-arrestin1 的结合延长了而不是终止了 PTHR 产生 cAMP，并且 cAMP 的产生与内体上 arrestin-受体复合物的持续存在相关。PTHR 信号转导是由 retromer 复合物关闭的，该复合物调节内化受体从内体到高尔基体的运动。因此，retromer 复合物的结合调节了由内化的 GPCR 触发的 cAMP 的持续产生。
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