Muscle acetylcholine receptor conversion into chloride conductance at positive potentials by a single mutation

Charge selectivity forms the basis of cellular excitation or inhibition by Cys-loop ligand-gated ion channels (LGICs), and is essential for physiological receptor function. There are no reports of naturally occurring mutations in LGICs associated with the conversion of charge selectivity. Here, we r...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-10, Vol.116 (42), p.21228-21235
Main Authors: Cetin, Hakan, Epstein, Max, Liu, Wei W., Maxwell, Susan, Cruz, Pedro M. Rodriguez, Cossins, Judith, Vincent, Angela, Webster, Richard, Biggin, Philip C., Beeson, David
Format: Article
Language:English
Subjects:
Acetylcholine - metabolism
Acetylcholine receptors
Biological Sciences
Cell Line
Chloride conductance
Chlorides
Chlorides - metabolism
Conversion
Electrostatic properties
Genetic transformation
HEK293 Cells
Humans
Ion Channel Gating - physiology
Ion channels
Ion channels (ligand-gated)
Ions
Membrane Potentials - physiology
Molecular dynamics
Muscles
Muscles - metabolism
Mutation
Mutation - genetics
Myasthenic Syndromes, Congenital - metabolism
Patch-Clamp Techniques - methods
PNAS Plus
Receptors, Cholinergic - metabolism
Receptors, Nicotinic - metabolism
Resistance
Selectivity
Sodium
Sodium - metabolism
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Summary:Charge selectivity forms the basis of cellular excitation or inhibition by Cys-loop ligand-gated ion channels (LGICs), and is essential for physiological receptor function. There are no reports of naturally occurring mutations in LGICs associated with the conversion of charge selectivity. Here, we report on a CHRNA1 mutation (α1Leu251Arg) in a patient with congenital myasthenic syndrome associated with transformation of the muscle acetylcholine receptor (AChR) into an inhibitory channel. Performing patch-clamp experiments, the AChR was found to be converted into chloride conductance at positive potentials, whereas whole-cell currents at negative potentials, although markedly reduced, were still carried by sodium. Umbrella sampling molecular dynamics simulations revealed constriction of the channel pore radius to 2.4 Å as a result of the mutation, which required partial desolvation of the ions in order to permeate the pore. Ion desolvation was associated with an energetic penalty that was compensated for by the favorable electrostatic interaction of the positively charged arginines with chloride. These findings reveal a mechanism for the transformation of the muscle AChR into an inhibitory channel in a clinical context.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1908284116