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

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

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From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
Department of Molecular Physiology and Biophysics.
Department of Molecular Physiology and Biophysics,
Center for Structural Biology, and.
Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and


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.


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

[Available on 2019-10-12]

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