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Structure-function Analyses of the Ion Channel TRPC3 Reveal That Its Cytoplasmic Domain Allosterically Modulates Channel Gating

Structure-function Analyses of the Ion Channel TRPC3 Reveal That Its Cytoplasmic Domain Allosterically Modulates Channel Gating

Francisco Sierra-Valdez, Caleigh M Azumaya, Luis O Romero, Terunaga Nakagawa, Julio F Cordero-Morales

J Biol Chem. 2018 Oct 12;293(41):16102-16114.

PMID: 30139744

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP924377855	GSK1702934A		924377-85-5	Price

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