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Constitutive signal bias mediated by the human GHRHR splice variant 1

By 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

Posted 20 Aug 2021
bioRxiv DOI: 10.1101/2021.08.20.457043

Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates Gs while SV1 selectively couples to {beta}-arrestins. Based on the cryo-electron microscopy structures of SV1 in the apo state or in complex with the Gs protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, Gs vs. {beta}-arrestins. Suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias towards {beta}-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation.

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