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This Article Full Text Full Text (PDF) All Versions of this Article: 564/2/377    most recent jphysiol.2004.081497v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shelley, C. Articles by Colquhoun, D. Search for Related Content PubMed PubMed Citation Articles by Shelley, C. Articles by Colquhoun, D.

¹ Department of Pharmacology, University College London, London WC1E 6BT, UK

A mutation in the epsilon subunit of the human nicotinic acetylcholine receptor (L78P) 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.

(Received 16 December 2004; accepted after revision 17 February 2005; first published online 24 February 2005)
Corresponding author D. Colquhoun: Department of Pharmacology, University College London, London WC1E 6BT, UK. Email: d.colquhoun{at}ucl.ac.uk

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