Structural basis for excitatory neuropeptide signaling
Open accessPublished version of a preprint
Abstract
Rapid signaling between neurons is mediated by ligand-gated ion channels, cell-surface proteins with an extracellular ligand-binding domain and a membrane-spanning ion channel domain. The degenerin/epithelial sodium channel (DEG/ENaC) superfamily is diverse in terms of its gating stimuli, with some DEG/ENaCs gated by neuropeptides, and others gated by pH, mechanical force or enzymatic activity. The mechanism by which ligands bind to and activate DEG/ENaCs is poorly understood. Here we dissected the structural basis for neuropeptide-gated activity of a neuropeptide-gated DEG/ENaC, FMRFamide-gated sodium channel 1 (FaNaC1) from the annelid worm Malacoceros fuliginosus , using cryo-electron microscopy. Structures of FaNaC1 in the ligand-free resting state and in several ligand-bound states reveal the ligand-binding site and capture the ligand-induced conformational changes of channel gating, which we verified with complementary mutagenesis experiments. Our results illuminate channel gating in DEG/ENaCs and offer a structural template for experimental dissection of channel pharmacology and ion conduction.
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Cites
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- Authors
- Kalienkova, V., Dandamudi, M., Paulino, C., & Lynagh, T.
- Affiliations
- University of Groningen (NL)
- University of Bergen (NO)
- Corresponding author
- Paulino, Cristina
- Lynagh, Timothy
- Venue
- Nature Structural & Molecular Biology
- Published
- 2024-02-09
- Volume
- 31
- Issue
- 4
- Pages
- 717-726
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC11026163
- OpenAlex
- W4391680694
- Cited by
- 12
- References
- 5
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 3
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (722.017.001, 740.018.016, 203053, 234817)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (722.017.001, 740.018.016)
- Norges Forskningsråd (234817)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- Malacoceros fuliginosus, ligand binding sites, channel gating, ligand-induced conformational change, ionic conduction
- MeSH terms
- Ligands, Neuropeptides, Ion Channel Gating, Cryoelectron Microscopy, Epithelial Sodium Channels
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