Abstract
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 β-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the apo state or GHRH-bound state in complex with the Gs protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, Gs 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.
Highlights
Alternative splicing of G protein–coupled receptors has been observed, but their functions are largely unknown
To better understand the functional outcome of alternative splicing of growth hormone–releasing hormone receptor (GHRHR), we evaluated the ability of SV1 to activate Gs upon stimulation by GHRH in the human embryonic kidney 293tsA1609neo (HEK293T) cells
A recent study demonstrates that alternative splicing of GHRHR, promoted by hypoxic microenvironment in solid tumors, is a cellular adaptation mechanism that induces cancer cell proliferation and migration [17]
Summary
Alternative splicing of G protein–coupled receptors has been observed, but their functions are largely unknown. Gprotein–coupled receptors (GPCRs) are the largest superfamily of proteins in the body They are almost expressed in every cell/tissue and transduce various signals to regulate a plethora of physiological functions [1]. While alternative splicing of the C-X-C chemokine receptor 3 (CXCR3) was linked to β-arrestin recruitment [4], expression of GHRHR splice variants could be induced by hypoxic microenvironment in solid tumors, leading enhanced glycolysis [17], suggesting that cancer-associated GPCR isoforms are a consequence of cellular adaptation and have an effect on malignancy. While the primary role of GHRHR is to stimulate growth hormone synthesis and secretion from the anterior pituitary somatotrophs upon GHRH binding [19], its ectopic expression in cancers has been studied extensively [20, 21]. 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
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