期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：40
DOI：10.1073/pnas.2106606118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
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 G
s while SV1 selectively couples to β-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the
apo state or GHRH-bound state in complex with the G
s protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, G
s versus β-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward β-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.
