Molecular architecture of the Gαi-bound TRPC5 ion channel
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). Howev...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38281-3 |
| _version_ | 1797832032761413632 |
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| author | Jongdae Won Jinsung Kim Hyeongseop Jeong Jinhyeong Kim Shasha Feng Byeongseok Jeong Misun Kwak Juyeon Ko Wonpil Im Insuk So Hyung Ho Lee |
| author_facet | Jongdae Won Jinsung Kim Hyeongseop Jeong Jinhyeong Kim Shasha Feng Byeongseok Jeong Misun Kwak Juyeon Ko Wonpil Im Insuk So Hyung Ho Lee |
| author_sort | Jongdae Won |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T14:01:13Z |
| format | Article |
| id | doaj.art-8e6d548a17d64ee88281a7d6e6b05ebe |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T14:01:13Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8e6d548a17d64ee88281a7d6e6b05ebe2023-05-07T11:17:11ZengNature PortfolioNature Communications2041-17232023-05-0114111610.1038/s41467-023-38281-3Molecular architecture of the Gαi-bound TRPC5 ion channelJongdae Won0Jinsung Kim1Hyeongseop Jeong2Jinhyeong Kim3Shasha Feng4Byeongseok Jeong5Misun Kwak6Juyeon Ko7Wonpil Im8Insuk So9Hyung Ho Lee10Department of Chemistry, College of Natural Sciences, Seoul National UniversityDepartment of Physiology, College of Medicine, Seoul National UniversityCenter for Research Equipment, Korea Basic Science InstituteDepartment of Physiology, College of Medicine, Seoul National UniversityDepartment of Biological Sciences and Chemistry, Lehigh UniversityDepartment of Physiology, College of Medicine, Seoul National UniversityDepartment of Physiology, College of Medicine, Seoul National UniversityDepartment of Physiology, College of Medicine, Seoul National UniversityDepartment of Biological Sciences and Chemistry, Lehigh UniversityDepartment of Physiology, College of Medicine, Seoul National UniversityDepartment of Chemistry, College of Natural Sciences, Seoul National UniversityAbstract 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.https://doi.org/10.1038/s41467-023-38281-3 |
| spellingShingle | Jongdae Won Jinsung Kim Hyeongseop Jeong Jinhyeong Kim Shasha Feng Byeongseok Jeong Misun Kwak Juyeon Ko Wonpil Im Insuk So Hyung Ho Lee Molecular architecture of the Gαi-bound TRPC5 ion channel Nature Communications |
| title | Molecular architecture of the Gαi-bound TRPC5 ion channel |
| title_full | Molecular architecture of the Gαi-bound TRPC5 ion channel |
| title_fullStr | Molecular architecture of the Gαi-bound TRPC5 ion channel |
| title_full_unstemmed | Molecular architecture of the Gαi-bound TRPC5 ion channel |
| title_short | Molecular architecture of the Gαi-bound TRPC5 ion channel |
| title_sort | molecular architecture of the gαi bound trpc5 ion channel |
| url | https://doi.org/10.1038/s41467-023-38281-3 |
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