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Mol Cell Neurosci
2006 Jan 01;321-2:82-90. doi: 10.1016/j.mcn.2006.02.004.
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Novel beta subunit mutation causes a slow-channel syndrome by enhancing activation and decreasing the rate of agonist dissociation.
Navedo MF
,
Lasalde-Dominicci JA
,
Báez-Pagán CA
,
Díaz-Pérez L
,
Rojas LV
,
Maselli RA
,
Staub J
,
Schott K
,
Zayas R
,
Gomez CM
.
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We traced the cause of a slow-channel syndrome (SCS) in a patient with progressive muscle weakness, repetitive compound muscle action potential and prolonged low amplitude synaptic currents to a V --> F substitution in the M1 domain of the beta subunit (betaV229F) of the muscle acetylcholine receptor (AChR). In vitro expression studies in Xenopus oocytes indicated that the novel mutation betaV229F expressed normal amounts of AChRs and decreased the ACh EC50 by 10-fold compared to wild type. Kinetic analysis indicated that the mutation displayed prolonged mean open duration and repeated openings during activation. Prolonged openings caused by the betaV229F mutation were due to a reduction in the channel closing rate and an increase in the effective channel opening rate. Repeated openings of the channel during activation were caused by a significant reduction in the agonist dissociation constant. In addition, the betaV229F mutation produced an increase in calcium permeability. The kinetic and permeation studies presented in this work are sufficient to explain the consequences of the betaV229F mutation on the miniature endplate currents and thus are direct evidence that the betaV229F mutation is responsible for compromising the safety margin of neuromuscular transmission in the patient.
Akabas,
Identification of acetylcholine receptor channel-lining residues in the M1 segment of the alpha-subunit.
1995, Pubmed,
Xenbase
Akabas,
Identification of acetylcholine receptor channel-lining residues in the M1 segment of the alpha-subunit.
1995,
Pubmed
,
Xenbase
Bouzat,
Nicotinic receptor fourth transmembrane domain: hydrogen bonding by conserved threonine contributes to channel gating kinetics.
2000,
Pubmed
Burzomato,
Single-channel behavior of heteromeric alpha1beta glycine receptors: an attempt to detect a conformational change before the channel opens.
2004,
Pubmed
Castro,
alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability.
1995,
Pubmed
Cens,
Ca(2+)-permeability of muscle nicotinic acetylcholine receptor is increased by expression of the epsilon subunit.
1997,
Pubmed
,
Xenbase
Colquhoun,
Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
1998,
Pubmed
Croxen,
Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome.
1997,
Pubmed
,
Xenbase
Croxen,
Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes.
2002,
Pubmed
Engel,
A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel.
1982,
Pubmed
Engel,
Sleuthing molecular targets for neurological diseases at the neuromuscular junction.
2003,
Pubmed
Engel,
New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome.
1996,
Pubmed
Gomez,
Active calcium accumulation underlies severe weakness in a panel of mice with slow-channel syndrome.
2002,
Pubmed
,
Xenbase
Gomez,
Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanisms.
2002,
Pubmed
,
Xenbase
Gomez,
A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome.
1995,
Pubmed
Gomez,
A beta-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome.
1996,
Pubmed
Hamill,
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
1981,
Pubmed
Hatton,
Properties of the human muscle nicotinic receptor, and of the slow-channel myasthenic syndrome mutant epsilonL221F, inferred from maximum likelihood fits.
2003,
Pubmed
Karlin,
Emerging structure of the nicotinic acetylcholine receptors.
2002,
Pubmed
Lee,
Principal pathway coupling agonist binding to channel gating in nicotinic receptors.
2005,
Pubmed
Milone,
Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetylcholine receptor alpha subunit.
1997,
Pubmed
Miyazawa,
Structure and gating mechanism of the acetylcholine receptor pore.
2003,
Pubmed
Ohno,
Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit.
1995,
Pubmed
Qin,
Estimating single-channel kinetic parameters from idealized patch-clamp data containing missed events.
1996,
Pubmed
,
Xenbase
Sigworth,
Data transformations for improved display and fitting of single-channel dwell time histograms.
1987,
Pubmed
Sine,
Mutation of the acetylcholine receptor alpha subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity.
1995,
Pubmed
Tamamizu,
Alteration in ion channel function of mouse nicotinic acetylcholine receptor by mutations in the M4 transmembrane domain.
1999,
Pubmed
,
Xenbase
Tzartos,
Monoclonal antibodies used to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits.
1980,
Pubmed
Wang,
Mutation in the M1 domain of the acetylcholine receptor alpha subunit decreases the rate of agonist dissociation.
1997,
Pubmed
Zhang,
Identification of acetylcholine receptor channel-lining residues in the M1 segment of the beta-subunit.
1997,
Pubmed
,
Xenbase