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Original Article

^a Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Foundation, Rochester, Minnesota 55905
^b Muscle Research Laboratory, Department of Neurology, Mayo Foundation, Rochester, Minnesota 55905
^c Institute of Neurology, Catholic University, 00168 Rome, Italy
^d Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus
Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Foundation, 200 First Street, S.W., Rochester, Minnesota 55905.507-284-9420, E-mail: sine.steven@mayo.edu

We describe the genetic and kinetic defects in a congenital myasthenic syndrome due to the mutation A411P in the amphipathic helix of the acetylcholine receptor (AChR) subunit. Myasthenic patients from three unrelated families are either homozygous for A411P or are heterozygous and harbor a null mutation in the second allele, indicating that A411P is recessive. We expressed human AChRs containing wild-type or A411P subunits in 293HEK cells, recorded single channel currents at high bandwidth, and determined microscopic rate constants for individual channels using hidden Markov modeling. For individual wild-type and mutant channels, each rate constant distributes as a Gaussian function, but the spread in the distributions for channel opening and closing rate constants is greatly expanded by A411P. Prolines engineered into positions flanking residue 411 of the subunit greatly increase the range of activation kinetics similar to A411P, whereas prolines engineered into positions equivalent to A411 in β and subunits are without effect. Thus, the amphipathic helix of the subunit stabilizes the channel, minimizing the number and range of kinetic modes accessible to individual AChRs. The findings suggest that analogous stabilizing structures are present in other ion channels, and possibly allosteric proteins in general, and that they evolved to maintain uniformity of activation episodes. The findings further suggest that the fundamental gating mechanism of the AChR channel can be explained by a corrugated energy landscape superimposed on a steeply sloped energy well.

Key Words: congenital myasthenic syndrome • single channel kinetics • hidden Markov modeling • channel gating • energy landscape

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