Structure-function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating

J Biol Chem. 2018 Oct 12;293(41):16102-16114. doi: 10.1074/jbc.RA118.005066. Epub 2018 Aug 23.


The transient receptor potential ion channels support Ca2+ permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily C member 3 (TRPC3) are associated with neurodegenerative diseases, memory loss, and hypertension. To better understand the conformational changes that regulate TRPC3 function, we solved the cryo-EM structures for the full-length human TRPC3 and its cytoplasmic domain (CPD) in the apo state at 5.8- and 4.0-Å resolution, respectively. These structures revealed that the TRPC3 transmembrane domain resembles those of other TRP channels and that the CPD is a stable module involved in channel assembly and gating. We observed the presence of a C-terminal domain swap at the center of the CPD where horizontal helices (HHs) transition into a coiled-coil bundle. Comparison of TRPC3 structures revealed that the HHs can reside in two distinct positions. Electrophysiological analyses disclosed that shortening the length of the C-terminal loop connecting the HH with the TRP helices increases TRPC3 activity and that elongating the length of the loop has the opposite effect. Our findings indicate that the C-terminal loop affects channel gating by altering the allosteric coupling between the cytoplasmic and transmembrane domains. We propose that molecules that target the HH may represent a promising strategy for controlling TRPC3-associated neurological disorders and hypertension.

Keywords: GSK-1702934A; TRPC3; calcium channel; cryo-electron microscopy; electrophysiology; ion channel; neurotransmitter; structural biology; transient receptor potential channels (TRP channels); vascular biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Ankyrin Repeat
  • HEK293 Cells
  • Humans
  • Ion Channel Gating*
  • Mutation
  • Protein Conformation, alpha-Helical
  • Protein Domains
  • TRPC Cation Channels / chemistry*
  • TRPC Cation Channels / genetics


  • TRPC Cation Channels
  • TRPC3 cation channel

Associated data

  • PDB/6CV9
  • PDB/6BCL
  • PDB/6CUD
  • PDB/6D7L
  • PDB/6DJR
  • PDB/6DJS