| First Author | Young A | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 9 | Pages | e24376 |
| PubMed ID | 21931697 | Mgi Jnum | J:177926 |
| Mgi Id | MGI:5296703 | Doi | 10.1371/journal.pone.0024376 |
| Citation | Young A, et al. (2011) Specific interaction of Galphai3 with the Oa1 G-protein coupled receptor controls the size and density of melanosomes in retinal pigment epithelium. PLoS One 6(9):e24376 |
| abstractText | BACKGROUND: Ocular albinism type 1, an X-linked disease characterized by the presence of enlarged melanosomes in the retinal pigment epithelium (RPE) and abnormal crossing of axons at the optic chiasm, is caused by mutations in the OA1 gene. The protein product of this gene is a G-protein-coupled receptor (GPCR) localized in RPE melanosomes. The Oa1-/- mouse model of ocular albinism reproduces the human disease. Oa1 has been shown to immunoprecipitate with the Galphai subunit of heterotrimeric G proteins from human skin melanocytes. However, the Galphai subfamily has three highly homologous members, Galphai1, Galphai2 and Galphai3 and it is possible that one or more of them partners with Oa1. We had previously shown by in-vivo studies that Galphai3-/- and Oa1-/- mice have similar RPE phenotype and decussation patterns. In this paper we analyze the specificity of the Oa1-Galphai interaction. METHODOLOGY: By using the genetic mouse models Galphai1-/-, Galphai2-/-, Galphai3-/- and the double knockout Galphai1-/-, Galphai3-/- that lack functional Galphai1, Galphai2, Galphai3, or both Galphai1 and Galphai3 proteins, respectively, we show that Galphai3 is critical for the maintenance of a normal melanosomal phenotype and that its absence is associated with changes in melanosomal size and density. GST-pull-down and immunoprecipitation assays conclusively demonstrate that Galphai3 is the only Galphai that binds to Oa1. Western blots show that Galphai3 expression is barely detectable in the Oa1-/- RPE, strongly supporting a previously unsuspected role for Galphai3 in melanosomal biogenesis. CONCLUSION: Our results identify the Oa1 transducer Galphai3 as the first downstream component in the Oa1 signaling pathway. |
