title: A human congenital myasthenia-causing mutation (epsilon L78P) of the muscle nicotinic acetylcholine receptor with unusual single channel properties.
abstract: A mutation in the epsilon subunit of the human nicotinic acetylcholine receptor (epsilonL78P) is known to cause a congenital slow channel myasthenic syndrome. We have investigated the changes in receptor function that result in the mutant receptor producing prolonged endplate currents, and consequent muscle damage. The rate constants for channel gating and for the binding and dissociation of acetylcholine were investigated by analysis of single ion channel recordings. A conventional mechanism with two non-equivalent binding sites, and variations upon this mechanism, were fitted to data using a maximum likelihood method that uses the Hawkes-Jalali-Colquhoun (HJC) treatment of missed brief events. The mutant receptor produced prolonged activations, bursts of openings that cause a slow decay of simulated synaptic currents. The main reason for the longer bursts of openings seen with mutant receptor was a decrease in the rate of ACh dissociation from diliganded receptors, though the lifetime of individual openings was somewhat increased too. As well as producing long bursts, the mutant receptor also produced many very short openings, though these carry little current. The burst structure for the mutant receptor at low ACh concentration is unusual in that most long bursts appear to start in a very brief monoliganded open state that then usually binds another ACh molecule to produce a long diliganded activation. The first opening is so short that it will usually be missed (together with the shut time that follows it), so the true burst length is likely to be underestimated.
authors.affiliation: Department of Pharmacology, University College London, London WC1E 6BT, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Shelley
authors.forename: David
authors.initials: D
authors.lastname: Colquhoun
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007930:Leucine / Q000235:genetics; D016013:Likelihood Functions; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics*; D011392:Proline / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000502:physiology
chemical_list: D011978:Receptors, Nicotinic; D011392:Proline; D007930:Leucine; D000109:Acetylcholine
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