4.6 Article

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

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 41, Pages 16102-16114

Publisher

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.005066

Keywords

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

Funding

  1. National Institutes of Health [R01 HD061543, 1-R01GM125629-01]
  2. Vanderbilt University Trans-Institutional Program
  3. American Heart Association [15SDG25700146]
  4. National Institutes of Health Molecular Biophysics Training Program Grant [T32 GM008320]
  5. EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [R01HD061543] Funding Source: NIH RePORTER
  6. NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR031634] Funding Source: NIH RePORTER
  7. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008320, R01GM125629] Funding Source: NIH RePORTER

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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-angstrom 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.

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