TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

Nobuaki Takahashi, Sayaka Hamada-Nakahara, Yuzuru Itoh, Kazuhiro Takemura, Atsushi Shimada, Yoshifumi Ueda, Manabu Kitamata, Rei Matsuoka, Kyoko Hanawa-Suetsugu, Yosuke Senju, Masayuki X. Mori, Shigeki Kiyonaka, Daisuke Kohda, Akio Kitao, Yasuo Mori, Shiro Suetsugu

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    42 Citations (Scopus)

    Abstract

    Mutations in the ankyrin repeat domain (ARD) of TRPV4 are responsible for several channelopathies, including Charcot-Marie-Tooth disease type 2C and congenital distal and scapuloperoneal spinal muscular atrophy. However, the molecular pathogenesis mediated by these mutations remains elusive, mainly due to limited understanding of the TRPV4 ARD function. Here we show that phosphoinositide binding to the TRPV4 ARD leads to suppression of the channel activity. Among the phosphoinositides, phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) most potently binds to the TRPV4 ARD. The crystal structure of the TRPV4 ARD in complex with inositol-1,4,5-trisphosphate, the head-group of PI(4,5)P2, and the molecular-dynamics simulations revealed the PI(4,5)P2 -binding amino-acid residues. The TRPV4 channel activities were increased by titration or hydrolysis of membrane PI(4,5)P2. Notably, disease-associated TRPV4 mutations that cause a gain-of-function phenotype abolished PI(4,5)P2 binding and PI(4,5)P2 sensitivity. These findings identify TRPV4 ARD as a lipid-binding domain in which interactions with PI(4,5)P2 normalize the channel activity in TRPV4.

    Original languageEnglish
    Article number4994
    JournalNature communications
    Volume5
    DOIs
    Publication statusPublished - 2014

    All Science Journal Classification (ASJC) codes

    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Physics and Astronomy(all)

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  • Cite this

    Takahashi, N., Hamada-Nakahara, S., Itoh, Y., Takemura, K., Shimada, A., Ueda, Y., Kitamata, M., Matsuoka, R., Hanawa-Suetsugu, K., Senju, Y., Mori, M. X., Kiyonaka, S., Kohda, D., Kitao, A., Mori, Y., & Suetsugu, S. (2014). TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2. Nature communications, 5, [4994]. https://doi.org/10.1038/ncomms5994