title: Constitutive Gαi coupling activity of very large G protein-coupled receptor 1 (VLGR1) and its regulation by PDZD7 protein.
abstract: The very large G protein-coupled receptor 1 (VLGR1) is a core component in inner ear hair cell development. Mutations in the vlgr1 gene cause Usher syndrome, the symptoms of which include congenital hearing loss and progressive retinitis pigmentosa. However, the mechanism of VLGR1-regulated intracellular signaling and its role in Usher syndrome remain elusive. Here, we show that VLGR1 is processed into two fragments after autocleavage at the G protein-coupled receptor proteolytic site. The cleaved VLGR1 β-subunit constitutively inhibited adenylate cyclase (AC) activity through Gαi coupling. Co-expression of the Gαiq chimera with the VLGR1 β-subunit changed its activity to the phospholipase C/nuclear factor of activated T cells signaling pathway, which demonstrates the Gαi protein coupling specificity of this subunit. An R6002A mutation in intracellular loop 2 of VLGR1 abolished Gαi coupling, but the pathogenic VLGR1 Y6236fsx1 mutant showed increased AC inhibition. Furthermore, overexpression of another Usher syndrome protein, PDZD7, decreased the AC inhibition of the VLGR1 β-subunit but showed no effect on the VLGR1 Y6236fsx1 mutant. Taken together, we identified an independent Gαi signaling pathway of the VLGR1 β-subunit and its regulatory mechanisms that may have a role in the development of Usher syndrome.
authors: From the Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology and.
authors: Qiao-Xia
authors: QX
authors: Hu
authors: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China, Weifang Medical University, Weifang, Shandong 261053, China.
authors: Jun-Hong
authors: JH
authors: Dong
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Shandong University School of Life Sciences, Jinan, Shandong 250100, China.
authors: Hai-Bo
authors: HB
authors: Du
authors: From the Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology and Binzhou Medical University, Yantai, Shandong 264003, China, and.
authors: Dao-Lai
authors: DL
authors: Zhang
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Shandong University School of Life Sciences, Jinan, Shandong 250100, China.
authors: Hong-Ze
authors: HZ
authors: Ren
authors: From the Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology and.
authors: Ming-Liang
authors: ML
authors: Ma
authors: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Yuan
authors: Y
authors: Cai
authors: From the Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology and.
authors: Tong-Chao
authors: TC
authors: Zhao
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Shandong University School of Life Sciences, Jinan, Shandong 250100, China.
authors: Xiao-Lei
authors: XL
authors: Yin
authors: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors: Xiao
authors: X
authors: Yu
authors: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Tian
authors: T
authors: Xue
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Shandong University School of Life Sciences, Jinan, Shandong 250100, China, xuzg@sdu.edu.cn.
authors: Zhi-Gang
authors: ZG
authors: Xu
authors: From the Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology and sunjinpeng@sdu.edu.cn.
authors: Jin-Peng
authors: JP
authors: Sun
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017931:DNA Primers; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D059748:Proteolysis; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology*
chemical_list: C417525:ADGRV1 protein, human; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D044385:GTP-Binding Protein alpha Subunits; C000594656:PDZD7 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: Adhesion; Cell Signaling; G Protein; G Protein-coupled Receptor (GPCR); Hearing; VLGR1, PDZD7, GPCR, Adhesion, Usher Syndrome