ArticleThe Journal of general physiology2006
Desensitization contributes to the synaptic response of gain-of-function mutants of the muscle nicotinic receptor.
Article in The Journal of general physiology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Structure and function at the lipid-protein interface of a pentameric ligand-gated ion channel.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Signal transduction through Cys-loop receptors is mediated by the nonspecific bumping of closely apposed domains.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Pathways for nicotinic receptor desensitization.The Journal of general physiology · 2020Article
- The Structure, Function, and Physiology of the Fetal and Adult Acetylcholine Receptor in Muscle.Frontiers in molecular neuroscience · 2020Review
- Article
- A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip.The Journal of general physiology · 2017Article
- Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia.The Journal of biological chemistry · 2016Article
- The atypical cation-conduction and gating properties of ELIC underscore the marked functional versatility of the pentameric ligand-gated ion-channel fold.The Journal of general physiology · 2015Article
- Mechanism of activation of the prokaryotic channel ELIC by propylamine: a single-channel study.The Journal of general physiology · 2015Article
- The role of intracellular linkers in gating and desensitization of human pentameric ligand-gated ion channels.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- GABAA receptor α and γ subunits shape synaptic currents via different mechanisms.The Journal of biological chemistry · 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
- An outline of desensitization in pentameric ligand-gated ion channel receptors.Cellular and molecular life sciences : CMLS · 2013Review
- The unanticipated complexity of the selectivity-filter glutamates of nicotinic receptors.Nature chemical biology · 2012Article
- Tunable pKa values and the basis of opposite charge selectivities in nicotinic-type receptors.Nature · 2011Article
- Desensitization of neurotransmitter-gated ion channels during high-frequency stimulation: a comparative study of Cys-loop, AMPA and purinergic receptors.The Journal of physiology · 2011Article
- Bridging the gap between structural models of nicotinic receptor superfamily ion channels and their corresponding functional states.Journal of molecular biology · 2010Article
- Structural basis of activation of cys-loop receptors: the extracellular-transmembrane interface as a coupling region.Molecular neurobiology · 2009Review
- Decremental response to high-frequency trains of acetylcholine pulses but unaltered fractional Ca2+ currents in a panel of "slow-channel syndrome" nicotinic receptor mutants.The Journal of general physiology · 2009Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Although the muscle nicotinic receptor (AChR) desensitizes almost completely in the steady presence of high concentrations of acetylcholine (ACh), it is well established that AChRs do not accumulate in desensitized states under normal physiological conditions of neurotransmitter release and clearance. Quantitative considerations in the framework of plausible kinetic schemes, however, lead us to predict that mutations that speed up channel opening, slow down channel closure, and/or slow down the dissociation of neurotransmitter (i.e., gain-of-function mutations) increase the extent to which AChRs desensitize upon ACh removal. In this paper, we confirm this prediction by applying high-frequency trains of brief ( approximately 1 ms) ACh pulses to outside-out membrane patches expressing either lab-engineered or naturally occurring (disease-causing) gain-of-function mutants. Entry into desensitization was evident in our experiments as a frequency-dependent depression in the peak value of succesive macroscopic current responses, in a manner that is remarkably consistent with the theoretical expectation. We conclude that the comparatively small depression of the macroscopic currents observed upon repetitive stimulation of the wild-type AChR is due, not to desensitization being exceedingly slow but, rather, to the particular balance between gating, entry into desensitization, and ACh dissociation rate constants. Disruption of this fine balance by, for example, mutations can lead to enhanced desensitization even if the kinetics of entry into, and recovery from, desensitization themselves are not affected. It follows that accounting for the (usually overlooked) desensitization phenomenon is essential for the correct interpretation of mutagenesis-driven structure-function relationships and for the understanding of pathological synaptic transmission at the vertebrate neuromuscular junction.
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