Dao-Lai Zhang,Yu-Jing Sun,Ming-Liang Ma,Yi-jing Wang,Hui Lin,Rui-Rui Li,Zong-Lai Liang,Yuan Gao,Zhao Yang,Dong-Fang He,Amy Lin,Hui Mo,Yu-Jing Lu,Meng-Jing Li,Wei Kong,Ka Young Chung,Fan Yi,Jian-Yuan Li,Ying-Ying Qin,Jingxin Li,Alex R B Thomsen,Alem W Kahsai,Zi-Jiang Chen,Zhi-Gang Xu,Mingyao Liu,Dali Li,Xiao Yu,Jin-Peng Sun
Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.
Summary Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by β cells. By screening the expression and functional characterization of olfactory receptors (ORs) in pancreatic islets, we identified Olfr109 as the receptor that detects insulin peptides. The engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signaling and promoted islet-resident macrophage proliferation through a β cell-macrophage circuit and a β-arrestin-1-mediated CCL2 pathway, as evidenced by β-arrestin-1 −/− mouse models. Systemic Olfr109 deficiency or deficiency induced by Pdx1-Cre +/− Olfr109 fl/fl specifically alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita - and high-fat diet (HFD)-fed mice. We further determined the binding mode between insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic β cells use Olfr109 to autonomously detect self-secreted insulin peptides, and this detection arrests insulin secretion and crosstalks with macrophages to increase intra-islet inflammation.
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