A novel splice variant of Gaq-coupled Bombyx CAPA-PVK receptor 1 functions as a specific Gai/o-linked receptor for CAPA-PK
A novel splice variant of Gaq-coupled Bombyx CAPA-PVK receptor 1 functions as a specific Gai/o-linked receptor for CAPA-PK
复制标题
Gaq 偶联的 Bombyx CAPA-PVK 受体 1 的新型剪接变体可作为 CAPA-PK 的特定 Gai/o 连接受体
DOI：
10.1016/j.bbamcr.2020.118718
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发表时间：
2020-08-01
影响因子：
5.1
通讯作者：
Zhou, Naiming
中科院分区：
文献类型：
--
作者：
Cao, Zheng;Yan, Lili;Zhou, Naiming
选择性剪接使G蛋白偶联受体（GPCR）基因能够大大增加结构和功能不同的受体亚型的数量。然而，单个GPCR剪接变体在调节生理过程中的功能作用和相关性仍有待评估。BomCAPA-PVK-R1-Delta 341是一种天然存在的CAPA-PVK受体的可变剪接变体，已被证明是一种显性负性蛋白，可调节典型CAPA-PVK受体的细胞表面表达和功能。在本文中，使用功能测定，我们鉴定剪接变体Delta 341为神经肽CAPA-PK的特异性受体，并且在激活时，Delta 341向ERK 1/2途径发出信号。进一步的表征表明，Delta 341与Gai/o偶联，与Gaq偶联的经典CAPA-PVK受体不同，通过G β γ-PI 3 K-PKC触发ERK 1/2磷酸化。信号级联此外，我们的ELISA数据显示，由于缺乏GRK介导的磷酸化位点，剪接变体Delta 341的配体依赖性内化显著受损。我们的研究结果突出了这种知识的潜力，在未来的GPCR剪接变异体的分子，药理学和生理学研究。
Alternative splicing enables G protein-coupled receptor (GPCR) genes to greatly increase the number of structurally and functionally distinct receptor isoforms. However, the functional role and relevance of the individual GPCR splice variants in regulating physiological processes are still to be assessed. A naturally occurring alternative splice variant of Bombyx CAPA-PVK receptor, BomCAPA-PVK-R1-Delta 341, has been shown to act as a dominant-negative protein to regulate cell surface expression and function of the canonical CAPA-PVK receptor. Herein, using functional assays, we identify the splice variant Delta 341 as a specific receptor for neuropeptide CAPA-PK, and upon activation, Delta 341 signals to ERK1/2 pathway. Further characterization demonstrates that Delta 341 couples to Gai/o, distinct from the Gaq-coupled canonical CAPA-PVK receptor, triggering ERK1/2 phosphorylation through G beta gamma-PI3K-PKC. signaling cascade. Moreover, our ELISA data show that the ligand-dependent internalization of the splice variant Delta 341 is significantly impaired due to lack of GRKs-mediated phosphorylation sites. Our findings highlight the potential of this knowledge for molecular, pharmacological and physiological studies on GPCR splice variants in the future.