Structure of the receptor-activated human TRPC6 and TRPC3 ion channels

Cell Res. 2018 Jul;28(7):746-755. doi: 10.1038/s41422-018-0038-2. Epub 2018 Apr 26.

Abstract

TRPC6 and TRPC3 are receptor-activated nonselective cation channels that belong to the family of canonical transient receptor potential (TRPC) channels. They are activated by diacylglycerol, a lipid second messenger. TRPC6 and TRPC3 are involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high-affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 Å resolution. We also present the structure of human TRPC3 at 4.4 Å resolution. These structures show two-layer architectures in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domains, including the N-terminal ankyrin repeats and the C-terminal coiled-coil, contribute to the tetramer assembly. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structures uncover the molecular architecture of TRPC channels and provide a structural basis for understanding the mechanism of these channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cryoelectron Microscopy / methods
  • HEK293 Cells
  • Humans
  • Protein Domains
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Sf9 Cells
  • Spodoptera
  • TRPC Cation Channels / antagonists & inhibitors*
  • TRPC Cation Channels / chemistry*
  • TRPC6 Cation Channel / antagonists & inhibitors*
  • TRPC6 Cation Channel / chemistry*

Substances

  • TRPC Cation Channels
  • TRPC3 cation channel
  • TRPC6 Cation Channel
  • TRPC6 protein, human