Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Am J Physiol Cell Physiol. 2022 Sep 1;323(3):C783-C790. doi: 10.1152/ajpcell.00452.2021. Epub 2022 Aug 1.
The canonical model for G protein-coupled receptors (GPCRs) activation assumes that stimulation of heterotrimeric G protein signaling upon ligand binding occurs solely at the cell surface and that duration of the stimulation is transient to prevent overstimulation. In this model, GPCR signaling is turned-off by receptor phosphorylation via GPCR kinases (GRKs) and subsequent recruitment of β-arrestins, resulting in receptor internalization into endosomes. Internalized receptors can then recycle back to the cell surface or be trafficked to lysosomes for degradation. However, over the last decade, this model has been extended by discovering that some internalized GPCRs continue to signal via G proteins from endosomes. This is the case for the parathyroid hormone (PTH) type 1 receptor (PTHR), which engages on sustained cAMP signaling from endosomes upon PTH stimulation. Accumulative evidence shows that the location of signaling has an impact on the physiological effects of GPCR signaling. This mini-review discusses recent insights into the mechanisms of PTHR endosomal signaling and its physiological impact.
G 蛋白偶联受体 (GPCR) 激活的规范模型假定，配体结合后异三聚体 G 蛋白信号的刺激仅发生在细胞表面，并且刺激的持续时间是短暂的，以防止过度刺激。在该模型中，GPCR 信号通过 GPCR 激酶 (GRKs) 对受体进行磷酸化，随后募集β-arrestin 来关闭，导致受体内化到内体中。内化的受体随后可以再循环回到细胞表面，或被运输到溶酶体进行降解。然而，在过去的十年中，通过发现一些内化的 GPCR 继续从内体通过 G 蛋白信号转导，这一模型得到了扩展。甲状旁腺激素 (PTH) 1 型受体 (PTHR) 就是这种情况，它在 PTH 刺激下从内体中持续产生 cAMP 信号。越来越多的证据表明，信号转导的位置对 GPCR 信号转导的生理效应有影响。这篇小型综述讨论了 PTHR 内体信号转导的机制及其生理影响的最新见解。
