Tyrosine phosphorylation-dependent activation of TRPC6 regulated by PLC-γ1 and nephrin: Effect of mutations associated with focal segmental glomerulosclerosis

Shoichiro Kanda, Yutaka Harita, Yoshio Shibagaki, Takashi Sekine, Takashi Igarashi, Takafumi Inoue, Seisuke Hattori

    Research output: Contribution to journalArticle

    34 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1824-1835
    Number of pages12
    JournalMolecular Biology of the Cell
    Volume22
    Issue number11
    DOIs
    Publication statusPublished - 2011 Jun 1

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    Focal Segmental Glomerulosclerosis
    Type C Phospholipases
    Tyrosine
    Podocytes
    Phosphorylation
    Mutation
    Foot
    Epithelial Cells
    Calcium
    Kidney
    Genes
    nephrin
    Proteins

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

    Cite this

    Tyrosine phosphorylation-dependent activation of TRPC6 regulated by PLC-γ1 and nephrin : Effect of mutations associated with focal segmental glomerulosclerosis. / Kanda, Shoichiro; Harita, Yutaka; Shibagaki, Yoshio; Sekine, Takashi; Igarashi, Takashi; Inoue, Takafumi; Hattori, Seisuke.

    In: Molecular Biology of the Cell, Vol. 22, No. 11, 01.06.2011, p. 1824-1835.

    Research output: Contribution to journalArticle

    Kanda, Shoichiro ; Harita, Yutaka ; Shibagaki, Yoshio ; Sekine, Takashi ; Igarashi, Takashi ; Inoue, Takafumi ; Hattori, Seisuke. / Tyrosine phosphorylation-dependent activation of TRPC6 regulated by PLC-γ1 and nephrin : Effect of mutations associated with focal segmental glomerulosclerosis. In: Molecular Biology of the Cell. 2011 ; Vol. 22, No. 11. pp. 1824-1835.
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