Molecular architecture of the Gαi-bound TRPC5 ion channel

• Published in: Nature communications Vol. 14; no. 1; pp. 2550 - 16
• Main Authors: Won, Jongdae, Kim, Jinsung, Jeong, Hyeongseop, Kim, Jinhyeong, Feng, Shasha, Jeong, Byeongseok, Kwak, Misun, Ko, Juyeon, Im, Wonpil, So, Insuk, Lee, Hyung Ho
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.05.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/45/269/1153; 631/535/1258/1259; Ankyrins; Cell Membrane - metabolism; Cell membranes; Crosstalk; Cryoelectron Microscopy; Electron microscopy; G protein-coupled receptors; Humanities and Social Sciences; Humans; Ion channels; Ions; Lipids; Membrane proteins; Molecular machines; Molecular structure; multidisciplinary; Phosphatidylinositol 4,5-diphosphate; Proteins; Receptors; Receptors, G-Protein-Coupled - metabolism; Science; Science (multidisciplinary); Stoichiometry; Switches; Transient Receptor Potential Channels; Transient receptor potential proteins; TRPC Cation Channels - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38281-3

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)-Gα i3 complexes with a 4:4 stoichiometry in lipid nanodiscs. Remarkably, Gα i3 binds to the ankyrin repeat edge of TRPC5 ~ 50 Å away from the cell membrane. Electrophysiological analysis shows that Gα i3 increases the sensitivity of TRPC5 to phosphatidylinositol 4,5-bisphosphate (PIP 2 ), thereby rendering TRPC5 more easily opened in the cell membrane, where the concentration of PIP 2 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. Ion channels could be directly regulated by the alpha subunit of heterotrimeric G-proteins. Here, authors present the cryo-EM structure of an ion channel-Gα complex, TRPC5-Gα i3 , and present functional insights into their direct interaction.