2. Academic Validation
  3. Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2

Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2

  • Cell Rep. 2018 Feb 6;22(6):1560-1573. doi: 10.1016/j.celrep.2018.01.042.
Wang Zheng 1,  Ruiqi Cai 2,  Laura Hofmann 3,  Vasyl Nesin 4,  Qiaolin Hu 2,  Wentong Long 5,  Mohammad Fatehi 5,  Xiong Liu 2,  Shaimaa Hussein 2,  Tim Kong 2,  Jingru Li 2,  Peter E Light 5,  Jingfeng Tang 6,  Veit Flockerzi 3,  Leonidas Tsiokas 4,  Xing-Zhen Chen 7
Affiliations

Affiliations

  • 1 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei 430068, China; Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
  • 2 Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
  • 3 Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg 66421, Germany.
  • 4 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
  • 5 Alberta Diabetes Institute, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • 6 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei 430068, China. Electronic address: jingfeng9930@163.com.
  • 7 National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei 430068, China; Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada. Electronic address: xzchen@ualberta.ca.
PMID: 29425510 DOI: 10.1016/j.celrep.2018.01.042
Abstract

Transient receptor potential (TRP) channels are regulated by diverse stimuli comprising thermal, chemical, and mechanical modalities. They are also commonly regulated by phosphatidylinositol-4,5-bisphosphate (PIP2), with underlying mechanisms largely unknown. We here revealed an intramolecular interaction of the TRPP3 N and C termini (N-C) that is functionally essential. The interaction was mediated by aromatic Trp81 in pre-S1 domain and cationic Lys568 in TRP-like domain. Structure-function analyses revealed similar N-C interaction in TRPP2 as well as TRPM8/-V1/-C4 via highly conserved tryptophan and lysine/arginine residues. PIP2 bound to cationic residues in TRPP3, including K568, thereby disrupting the N-C interaction and negatively regulating TRPP3. PIP2 had similar negative effects on TRPP2. Interestingly, we found that PIP2 facilitates the N-C interaction in TRPM8/-V1, resulting in channel potentiation. The intramolecular N-C interaction might represent a shared mechanism underlying the gating and PIP2 regulation of TRP channels.

Keywords

PIP2; TRP; TRP domain; electrophysiology; gating; intramolecular interaction; pre-S1.

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