Structural basis for excitatory neuropeptide signaling

• Verfasst von: Kalienkova, Valeria [VerfasserIn]
• Verfasst von: Dandamudi, Mowgli [VerfasserIn]
• Verfasst von: Batista Paulino, Cristina [VerfasserIn]
• Verfasst von: Lynagh, Timothy [VerfasserIn]
• Titel: Structural basis for excitatory neuropeptide signaling
• Verf.angabe: Valeria Kalienkova, Mowgli Dandamudi, Cristina Paulino & Timothy Lynagh
• E-Jahr: 2024
• Jahr: 09 February 2024
• Umfang: 29 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 18.06.2024
• Titel Quelle: Enthalten in: Nature structural & molecular biology
• Ort Quelle: London [u.a.] : Nature Publishing Group, 2004
• Jahr Quelle: 2024
• Band/Heft Quelle: 31(2024), 4, Seite 717-726, [1-19]
• ISSN Quelle: 1545-9985
• DOI: doi:10.1038/s41594-023-01198-y
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Cryoelectron microscopy
• Sach-SW: Ligand-gated ion channels
• K10plus-PPN: 1891413147

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.