Myasthenic nicotinic receptor mutant interpreted in terms of the allosteric model

C R Acad Sci III. 1997 Dec;320(12):953-61. doi: 10.1016/s0764-4469(97)82468-7.

Abstract

An extended Monod-Wyman-Changeux allosteric-type model is applied to human muscle nicotinic acetylcholine receptors expressed in HEK cells, for both the normal form and the high-affinity human myasthenic mutant, epsilon T264P. The model is based on a concerted transition between the basal (resting) B state and the active (open-channel) A state, with the equilibrium in the absence of ligand determined by the allosteric constant, L0 = [B0]/[A0]. For wild-type receptors the model with L0 = 9 x 10(8) provides a satisfactory representation of published patch-clamp recordings that yields a distribution of open-channel dwell times with a single peak at 0.7 ms. For the epsilon T264P mutant, the model with L0 = 100 accounts for the trimodal distribution reported for open-channel dwell times, with peaks at 0.15, 3.8 and 60 ms that correspond to non-, mono- and bi-liganded receptors, respectively. Possible applications of the allosteric model to other myasthenic mutants are considered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Humans
  • Ion Channel Gating
  • Models, Biological*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Mutation
  • Receptors, Cholinergic / genetics
  • Receptors, Cholinergic / metabolism*
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*

Substances

  • Muscle Proteins
  • Receptors, Cholinergic
  • Receptors, Nicotinic