ArticleThe Journal of physiology2003
Properties of the human muscle nicotinic receptor, and of the slow-channel myasthenic syndrome mutant epsilonL221F, inferred from maximum likelihood fits.
Article in The Journal of physiology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 89 citations in OpenAlex.
- Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.International journal of molecular sciences · 2023Review
- The surprising difficulty of "simple" equilibrium binding measurements on ligand-gated ion channels.The Journal of general physiology · 2022Article
- Probing function in ligand-gated ion channels without measuring ion transport.The Journal of general physiology · 2022Article
- Efficiency measures the conversion of agonist binding energy into receptor conformational change.The Journal of general physiology · 2019Article
- Clinical and genetic characterization of an Italian family with slow-channel syndrome.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2019Article
- Impaired NGF/TrkA Signaling Causes Early AD-Linked Presynaptic Dysfunction in Cholinergic Primary Neurons.Frontiers in cellular neuroscience · 2017Article
- Mutations Causing Slow-Channel Myasthenia Reveal That a Valine Ring in the Channel Pore of Muscle AChR is Optimized for Stabilizing Channel Gating.Human mutation · 2016Article
- Bayesian Statistical Inference in Ion-Channel Models with Exact Missed Event Correction.Biophysical journal · 2016Article
- Improved resolution of single channel dwell times reveals mechanisms of binding, priming, and gating in muscle AChR.The Journal of general physiology · 2016Article
- Potential new therapeutic modality revealed through agent-based modeling of the neuromuscular junction and acetylcholinesterase inhibition.Theoretical biology & medical modelling · 2014Article
- Agonists binding nicotinic receptors elicit specific channel-opening patterns at αγ and αδ sites.The Journal of physiology · 2014Article
- Single-channel properties of α3β4, α3β4α5 and α3β4β2 nicotinic acetylcholine receptors in mice lacking specific nicotinic acetylcholine receptor subunits.The Journal of physiology · 2013Article
- Perspectives on: conformational coupling in ion channels: allosteric coupling in ligand-gated ion channels.The Journal of general physiology · 2012Article
- End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease.Physiological reviews · 2012Review
- The intrinsic energy of the gating isomerization of a neuromuscular acetylcholine receptor channel.The Journal of general physiology · 2012Article
- Design and control of acetylcholine receptor conformational change.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Phenotypic heterogeneity in a large Thai slow-channel congenital myasthenic syndrome kinship.Neuromuscular disorders : NMD · 2011Article
- Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors.The Journal of physiology · 2010Article
- What have we learned from the congenital myasthenic syndromes.Journal of molecular neuroscience : MN · 2010Review
- What single-channel analysis tells us of the activation mechanism of ligand-gated channels: the case of the glycine receptor.The Journal of physiology · 2010Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The mechanisms that underlie activation of nicotinic receptors are investigated using human recombinant receptors, both wild type and receptors that contain the slow channel myasthenic syndrome mutation, epsilonL221F. The method uses the program HJCFIT, which fits the rate constants in a specified mechanism directly to a sequence of observed open and shut times by maximising the likelihood of the sequence with exact correction for missed events. A mechanism with two different binding sites was used. The rate constants that apply to the diliganded receptor (opening, shutting and total dissociation rates) were estimated robustly, being insensitive to the exact assumptions made during fitting, as expected from simulation studies. They are sufficient to predict the main physiological properties of the receptors. The epsilonL221F mutation causes an approximately 4-fold reduction in dissociation rate from diliganded receptors, and a smaller increase in opening rate and mean open time. These are sufficient to explain the approximately 6-fold slowing of decay of miniature synaptic currents seen in patients. The distinction between the two binding sites was less robust, the estimates of rate constants being dependent to some extent on assumptions, e.g. whether an extra short-lived shut state was included or whether the EC50 was constrained. The results suggest that the two binding sites differ by roughly 10-fold in the affinity of the shut receptor for ACh in the wild type, and that in the epsilonL221F mutation the lower affinity is increased so the sites become more similar.
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