Tyrosine phosphorylation–dependent activation of TRPC6 regulated by PLC-γ1 and nephrin: effect of mutations associated with focal segmental glomerulosclerosis
Open Access
- 1 June 2011
- journal article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 22 (11), 1824-1835
- https://doi.org/10.1091/mbc.e10-12-0929
Abstract
Transient receptor potential canonicals (TRPCs) play important roles in the regulation of intracellular calcium concentration. Mutations in the TRPC6 gene are found in patients with focal segmental glomerulosclerosis (FSGS), a proteinuric disease characterized by dysregulated function of renal glomerular epithelial cells (podocytes). There is as yet no clear picture for the activation mechanism of TRPC6 at the molecular basis, however, and the association between its channel activity and pathogenesis remains unclear. We demonstrate here that tyrosine phosphorylation of TRPC6 induces a complex formation with phospholipase C (PLC)-γ1, which is prerequisite for TRPC6 surface expression. Furthermore, nephrin, an adhesion protein between the foot processes of podocytes, binds to phosphorylated TRPC6 via its cytoplasmic domain, competitively inhibiting TRPC6–PLC-γ1 complex formation, TRPC6 surface localization, and TRPC6 activation. Importantly, FSGS-associated mutations render the mutated TRPC6s insensitive to nephrin suppression, thereby promoting their surface expression and channel activation. These results delineate the mechanism of TRPC6 activation regulated by tyrosine phosphorylation, and imply the cell type–specific regulation, which correlates the FSGS mutations with deregulated TRPC6 channel activity.Keywords
This publication has 58 references indexed in Scilit:
- CIN85/RukL Is a Novel Binding Partner of Nephrin and Podocin and Mediates Slit Diaphragm Turnover in PodocytesOnline Journal of Public Health Informatics, 2010
- Phosphorylation of TRPC6 Channels at Thr69 Is Required for Anti-hypertrophic Effects of Phosphodiesterase 5 InhibitionOnline Journal of Public Health Informatics, 2010
- Phospholipase C-γ Binds Directly to the Na+/H+ Exchanger 3 and Is Required for Calcium Regulation of Exchange ActivityOnline Journal of Public Health Informatics, 2009
- Phosphorylation of Nephrin Triggers Ca2+ Signaling by Recruitment and Activation of Phospholipase C-γ1Online Journal of Public Health Informatics, 2009
- Neph1, a Component of the Kidney Slit Diaphragm, Is Tyrosine-phosphorylated by the Src Family Tyrosine Kinase and Modulates Intracellular Signaling by Binding to Grb2Online Journal of Public Health Informatics, 2008
- Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channelsProceedings of the National Academy of Sciences of the United States of America, 2006
- TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophyThe EMBO Journal, 2006
- β-Arrestin2 mediates nephrin endocytosis and impairs slit diaphragm integrityProceedings of the National Academy of Sciences of the United States of America, 2006
- TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal functionNature Genetics, 2005
- Rapid vesicular translocation and insertion of TRP channelsNature, 2004