Retromer terminates the generation of cAMP by internalized PTH receptors.
Retromer terminates the generation of cAMP by internalized PTH receptors.
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逆转录者通过内部化的PTH受体终止cAMP的产生。
DOI：
10.1038/nchembio.545
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发表时间：
2011-05
影响因子：
14.8
通讯作者：
Vilardaga, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Feinstein, Timothy N.;Wehbi, Vanessa L.;Ardura, Juan A.;Wheeler, David S.;Ferrandon, Sebastien;Gardella, Thomas J.;Vilardaga, Jean-Pierre
目前认为，G蛋白偶联受体（gpcr）产生cAMP及其终止只发生在细胞的质膜上。在现有的受体调节模型中，该信号主要受到受体通过与β-阻滞蛋白结合而脱敏的限制。然而，这种模式与最近的观察结果不一致，即甲状旁腺激素受体1型（PTHR）即使在受体内化后仍能继续刺激cAMP的产生，因为已知β-抑制素能迅速结合并内化激活的PTHR。在这里，我们发现β-arrestin1结合延长而不是终止PTHR产生的cAMP，并且cAMP的产生与内体上的arrestin1受体复合物的持久性有关。我们发现PTHR信号被反向复合体关闭，反向复合体调节内化受体从核内体到高尔基体的交通。因此，逆转录复合物的结合调节由内化GPCR触发的持续cAMP生成。
Generation of cAMP by G protein–coupled receptors (GPCRs) and its termination is currently thought to occur exclusively at the plasma membrane of cells. Under existing models of receptor regulation, this signal is primarily restricted by desensitizationof 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 β-arrestin1 binding prolongs rather than terminates cAMP generation by PTHR, and that cAMP generation correlates with the persistence of arrestin-receptor complexes on endosomes. We found that PTHR signaling is instead turned-off by the retromer complex, which regulates traffic of internalized receptor from endosomes to the Golgi apparatus. Thus, binding by the retromer complex regulates sustained cAMP generation triggered by an internalized GPCR.
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