Constitutive signal bias mediated by the human GHRHR splice variant 1
Zhaotong Cong, Fulai Zhou, Chao Zhang, Xinyu Zou, Huibing Zhang, Yuzhe Wang, Qingtong Zhou, Xiaoqing Cai, Qiaofeng Liu, Jie Li, Lijun Shao, Chunyou Mao, Xi Wang, Jihong Wu, Tian Xia, Lihua Zhao, Hualiang Jiang, Yan Zhang, H. Eric Xu, Xi Cheng, Dehua Yang, Ming‐Wei Wang
Abstract
Significance The mechanism of functional changes induced by alternative splicing of GHRHR is largely unknown. Here, we demonstrate that GHRH-elicited signal bias toward β-arrestin recruitment is constitutively mediated by SV1. The cryogenic electron microscopy structures of SV1 and molecular dynamics simulations reveal the different functionalities between GHRHR and SV1 at the near-atomic level (i.e., the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, G s versus β-arrestins). Our findings provide valuable insights into the functional diversity of class B1 GPCRs that may aid in the design of better therapeutic agents against certain cancers.