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PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker

Author

Listed:
  • Amy Clarke

    (Medical University of Vienna)

  • Julia Skerjanz

    (Division of Medical Physics and Biophysics, Medical University of Graz)

  • Mathias A. F. Gsell

    (Division of Medical Physics and Biophysics, Medical University of Graz)

  • Patrick Wiedner

    (Division of Medical Physics and Biophysics, Medical University of Graz)

  • Hazel Erkan-Candag

    (Division of Medical Physics and Biophysics, Medical University of Graz)

  • Klaus Groschner

    (Division of Medical Physics and Biophysics, Medical University of Graz)

  • Thomas Stockner

    (Medical University of Vienna)

  • Oleksandra Tiapko

    (Division of Medical Physics and Biophysics, Medical University of Graz
    BioTechMed)

Abstract

The transient receptor potential canonical type 3 (TRPC3) channel plays a pivotal role in regulating neuronal excitability in the brain via its constitutive activity. The channel is intricately regulated by lipids and has previously been demonstrated to be positively modulated by PIP2. Using molecular dynamics simulations and patch clamp techniques, we reveal that PIP2 predominantly interacts with TRPC3 at the L3 lipid binding site, located at the intersection of pre-S1 and S1 helices. We demonstrate that PIP2 sensing involves a multistep mechanism that propagates from L3 to the pore domain via a salt bridge between the TRP helix and S4-S5 linker. Notably, we find that both stimulated and constitutive TRPC3 activity require PIP2. These structural insights into the function of TRPC3 are invaluable for understanding the role of the TRPC subfamily in health and disease, in particular for cardiovascular diseases, in which TRPC3 channels play a major role.

Suggested Citation

  • Amy Clarke & Julia Skerjanz & Mathias A. F. Gsell & Patrick Wiedner & Hazel Erkan-Candag & Klaus Groschner & Thomas Stockner & Oleksandra Tiapko, 2024. "PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49396-6
    DOI: 10.1038/s41467-024-49396-6
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    References listed on IDEAS

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    1. Jianhua Zhao & John V. Lin King & Candice E. Paulsen & Yifan Cheng & David Julius, 2020. "Irritant-evoked activation and calcium modulation of the TRPA1 receptor," Nature, Nature, vol. 585(7823), pages 141-145, September.
    2. Charles R. Harris & K. Jarrod Millman & Stéfan J. Walt & Ralf Gommers & Pauli Virtanen & David Cournapeau & Eric Wieser & Julian Taylor & Sebastian Berg & Nathaniel J. Smith & Robert Kern & Matti Picu, 2020. "Array programming with NumPy," Nature, Nature, vol. 585(7825), pages 357-362, September.
    3. Thomas Hofmann & Alexander G. Obukhov & Michael Schaefer & Christian Harteneck & Thomas Gudermann & Günter Schultz, 1999. "Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol," Nature, Nature, vol. 397(6716), pages 259-263, January.
    4. Cheng Zhao & Yuan Xie & Lizhen Xu & Fan Ye & Ximing Xu & Wei Yang & Fan Yang & Jiangtao Guo, 2022. "Structures of a mammalian TRPM8 in closed state," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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