Molecular architecture of the Gαi-bound TRPC5 ion channel

Jongdae Won, Jinsung Kim, Hyeongseop Jeong, Jinhyeong Kim, Shasha Feng, Byeongseok Jeong, Misun Kwak, Juyeon Ko, Wonpil Im, Insuk So () and Hyung Ho Lee ()
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Jongdae Won: Seoul National University
Jinsung Kim: Seoul National University
Hyeongseop Jeong: Korea Basic Science Institute
Jinhyeong Kim: Seoul National University
Shasha Feng: Lehigh University
Byeongseok Jeong: Seoul National University
Misun Kwak: Seoul National University
Juyeon Ko: Seoul National University
Wonpil Im: Lehigh University
Insuk So: Seoul National University
Hyung Ho Lee: Seoul National University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract G-protein coupled receptors (GPCRs) and ion channels serve as key molecular switches through which extracellular stimuli are transformed into intracellular effects, and it has long been postulated that ion channels are direct effector molecules of the alpha subunit of G-proteins (Gα). However, no complete structural evidence supporting the direct interaction between Gα and ion channels is available. Here, we present the cryo-electron microscopy structures of the human transient receptor potential canonical 5 (TRPC5)-Gαi3 complexes with a 4:4 stoichiometry in lipid nanodiscs. Remarkably, Gαi3 binds to the ankyrin repeat edge of TRPC5 ~ 50 Å away from the cell membrane. Electrophysiological analysis shows that Gαi3 increases the sensitivity of TRPC5 to phosphatidylinositol 4,5-bisphosphate (PIP2), thereby rendering TRPC5 more easily opened in the cell membrane, where the concentration of PIP2 is physiologically regulated. Our results demonstrate that ion channels are one of the direct effector molecules of Gα proteins triggered by GPCR activation–providing a structural framework for unraveling the crosstalk between two major classes of transmembrane proteins: GPCRs and ion channels.

Date: 2023
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DOI: 10.1038/s41467-023-38281-3

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