Two naturally occurring mutations of human GPR103 define distinct G protein selection bias
Two naturally occurring mutations of human GPR103 define distinct G protein selection bias
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人类 GPR103 的两个自然发生的突变定义了不同的 G 蛋白选择偏差
DOI：
10.1016/j.bbamcr.2021.119046
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Naiming Zhou
中科院分区：
文献类型：
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作者：
Qiang Ma;Zheng Cao;Huanzheng Li;Weiwei Wang;Yanan Tian;Lili Yan;Yuan Liao;Xiangnan Chen;Yu Chen;Ying Shi;Shaohua Tang;Naiming Zhou
神经肽26RFa在许多生理功能的调节中发挥着重要作用。 26RFa 已被认为是受体 GPR103 的内源配体。在本研究中，我们证明 GPR103 与 Gαq 和 Gαi/o 蛋白双重偶联。然而，在一名年轻男性患者身上发现了两种自然发生的错义突变。在第一个 Y68H 中，注意到 Ca2+ 动员的诱导，但未检测到 ERK1/2 激活。在第二个 R371W 中，激活 ERK1/2 信号传导的潜力得以保留，但未能引起 Ca2+ 动员。进一步的分析表明，Gαq、L 型 Ca2+ 通道以及 PKCβI 和 βII 参与 Y68H 介导的信号传导途径，而 Gαi/o、Gβγ 和 PKCζ 参与 R371W 诱导的信号传导。我们的结果表明，两个点突变 Y68H 和 R371W 影响不同受体构象之间的平衡，导致 G 蛋白偶联偏好的改变。重要的是，这些发现为未来阐明 GPCR 介导的偏向信号及其偏向的生理影响奠定了基础。
The neuropeptide 26RFa plays important roles in the regulation of many physiological functions. 26RFa has been recognized as an endogenous ligand for receptor GPR103. In the present study, we demonstrate that GPR103 dually couples to Gαq and Gαi/o proteins. However, two naturally occurring missense mutations were identified from a young male patient. In the first, Y68H, induction of Ca2+ mobilization was noted without detection of ERK1/2 activation. In the second, R371W, the potential to activate ERK1/2 signaling was retained but with failure to evoke Ca2+ mobilization. Further analysis provides evidence that Gαq, L-type Ca2+ channel and PKCβI and βII are involved in the Y68H-mediated signaling pathway, whereas Gαi/o, Gβγ, and PKCζ are implicated in.the R371W-induced signaling. Our results demonstrate that two point mutations, Y68H and R371W, affect the equilibrium between the different receptor conformations, leading to alteration of G protein-coupling preferences. Importantly, these findings provide a foundation for future elucidation of GPCR-mediated biased signaling and the physiological implications of their bias.