Structures of the human adult muscle-type nicotinic receptor in resting and desensitized states

• Published in: Cell reports (Cambridge) Vol. 44; no. 5; p. 115581
• Main Authors: Li, Anna, Pike, Ashley C.W., Webster, Richard, Maxwell, Susan, Liu, Wei-Wei, Chi, Gamma, Palace, Jacqueline, Beeson, David, Sauer, David B., Dong, Yin Yao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.05.2025; Elsevier
• Subjects: Acetylcholine - metabolism; acetylcholine receptor; Adult; Bungarotoxins - metabolism; congenital myasthenic syndromes; CP: Molecular biology; CP: Neuroscience; cryo-EM; electrophysiology; Humans; ion channel; Models, Molecular; Myasthenic Syndromes, Congenital - genetics; Myasthenic Syndromes, Congenital - metabolism; neuromuscular junction; nicotinic receptor; pLGIC; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; acetylcholine receptor; electrophysiology; ion channel; neuromuscular junction; CP: Neuroscience; pLGIC; congenital myasthenic syndromes; CP: Molecular biology; nicotinic receptor; cryo-EM
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2025.115581

Muscle-type nicotinic acetylcholine receptor (AChR) is the key signaling molecule in neuromuscular junctions. Here, we present the structures of full-length human adult receptors in complex with Fab35 in α-bungarotoxin (αBuTx)-bound resting states and ACh-bound desensitized states. In addition to identifying the conformational changes during recovery from desensitization, we also used electrophysiology to probe the effects of eight previously unstudied AChR genetic variants found in patients with congenital myasthenic syndrome (CMS), revealing they cause either slow- or fast-channel CMS characterized by prolonged or abbreviated ion channel bursts. The combined kinetic and structural data offer a better understanding of both the AChR state transition and the pathogenic mechanisms of disease variants. [Display omitted] •Expression of the human adult muscle-type AChR using a stable cell line•Cryo-EM structures show conformational changes during recovery from desensitization•Electrophysiological characterization of unreported congenital myasthenic syndrome variants•N-terminal ATCUN sequence motif of the α subunit is capable of coordinating Cu2+ Mutations in the muscle-type AChR are associated with a rare neuromuscular disorder known as congenital myasthenic syndrome (CMS). Li et al. report the cryo-EM structures of human adult muscle-type AChR in resting and desensitized states and provide structural explanations for eight unreported CMS variants causing gain or loss of function in AChR.