ArticleThe Journal of clinical investigation2003
Mutation causing severe myasthenia reveals functional asymmetry of AChR signature cystine loops in agonist binding and gating.
Article in The Journal of clinical investigation, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 72 citations in OpenAlex.
- Article
- Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.International journal of molecular sciences · 2023Review
- Mutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor ε-subunit.JCI insight · 2018Article
- Signal Transduction at the Domain Interface of Prokaryotic Pentameric Ligand-Gated Ion Channels.PLoS biology · 2016Article
- Investigation of Congenital Myasthenia Reveals Functional Asymmetry of Invariant Acetylcholine Receptor (AChR) Cys-loop Aspartates.The Journal of biological chemistry · 2016Article
- Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment.The Lancet. Neurology · 2015Review
- Energetic contributions to channel gating of residues in the muscle nicotinic receptor β1 subunit.PloS one · 2013Article
- Myasthenic syndrome AChRα C-loop mutant disrupts initiation of channel gating.The Journal of clinical investigation · 2012Article
- Functional consequences and structural interpretation of mutations of human choline acetyltransferase.Human mutation · 2011Article
- A Cys-loop mutation in the Caenorhabditis elegans nicotinic receptor subunit UNC-63 impairs but does not abolish channel function.The Journal of biological chemistry · 2011Article
- Glycosylation of {beta}2 subunits regulates GABAA receptor biogenesis and channel gating.The Journal of biological chemistry · 2010Article
- Unresponsive correlated motion in alpha7 nAChR to halothane binding explains its functional insensitivity to volatile anesthetics.The journal of physical chemistry. B · 2010Article
- Anionic lipids allosterically modulate multiple nicotinic acetylcholine receptor conformational equilibria.The Journal of biological chemistry · 2009Article
- Structural basis of activation of cys-loop receptors: the extracellular-transmembrane interface as a coupling region.Molecular neurobiology · 2009Review
- hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome.Human molecular genetics · 2008Article
- Altered ivermectin pharmacology and defective visual system in Drosophila mutants for histamine receptor HCLB.Invertebrate neuroscience : IN · 2008Article
- Individually monitoring ligand-induced changes in the structure of the GABAA receptor at benzodiazepine binding site and non-binding-site interfaces.Molecular pharmacology · 2008Article
- Congenital myasthenia-related AChR delta subunit mutation interferes with intersubunit communication essential for channel gating.The Journal of clinical investigation · 2008Article
- Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders.American journal of human genetics · 2008Article
- A sequence variation in the MOG gene is involved in multiple sclerosis susceptibility in Italy.Genes and immunity · 2008Article
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7 authors at 1 institution in 1 country.
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Abstract
We describe a highly disabling congenital myasthenic syndrome (CMS) associated with rapidly decaying, low-amplitude synaptic currents, and trace its cause to a valine to leucine mutation in the signature cystine loop (cys-loop) of the AChR alpha subunit. The recently solved crystal structure of an ACh-binding protein places the cys-loop at the junction between the extracellular ligand-binding and transmembrane domains where it may couple agonist binding to channel gating. We therefore analyzed the kinetics of ACh-induced single-channel currents to identify elementary steps in the receptor activation mechanism altered by the alphaV132L mutation. The analysis reveals that alphaV132L markedly impairs ACh binding to receptors in the resting closed state, decreasing binding affinity for the second binding step 30-fold, but attenuates gating efficiency only about twofold. By contrast, mutation of the equivalent valine residue in the delta subunit impairs channel gating approximately fourfold with little effect on ACh binding, while corresponding mutations in the beta and epsilon subunits are without effect. The unique functional contribution of the alpha subunit cys-loop likely owes to its direct connection via a beta strand to alphaW149 at the center of the ligand-binding domain. The overall findings reveal functional asymmetry between cys-loops of the different AChR subunits in contributing to ACh binding and channel gating.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.