| First Author | Hu QX | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 35 | Pages | 24215-25 |
| PubMed ID | 24962568 | Mgi Jnum | J:266111 |
| Mgi Id | MGI:6212875 | Doi | 10.1074/jbc.M114.549816 |
| Citation | Hu QX, et al. (2014) Constitutive Galphai coupling activity of very large G protein-coupled receptor 1 (VLGR1) and its regulation by PDZD7 protein. J Biol Chem 289(35):24215-25 |
| abstractText | 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 beta-subunit constitutively inhibited adenylate cyclase (AC) activity through Galphai coupling. Co-expression of the Galphaiq chimera with the VLGR1 beta-subunit changed its activity to the phospholipase C/nuclear factor of activated T cells signaling pathway, which demonstrates the Galphai protein coupling specificity of this subunit. An R6002A mutation in intracellular loop 2 of VLGR1 abolished Galphai 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 beta-subunit but showed no effect on the VLGR1 Y6236fsx1 mutant. Taken together, we identified an independent Galphai signaling pathway of the VLGR1 beta-subunit and its regulatory mechanisms that may have a role in the development of Usher syndrome. |
