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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.

Author information

1
From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
2
Department of Molecular Physiology and Biophysics.
3
Department of Molecular Physiology and Biophysics, terunaga.nakagawa@vanderbilt.edu.
4
Center for Structural Biology, and.
5
Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
6
From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and jcordero@uthsc.edu.

Abstract

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

PMID:
30139744
PMCID:
PMC6187627
[Available on 2019-10-12]
DOI:
10.1074/jbc.RA118.005066

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