Myasthenic nicotinic receptor mutant interpreted in terms of the allosteric model

Abstract

An extended Monod—Wymctn—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 myasthénic mutant, ε 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, L o = [B 0]/[A 0]. For wild-type receptors the model with L 0 = 910 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 εT264P mutant, the model with L 0 = 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 myasthénic mutants are considered.