MYASTHENIC NICOTINIC RECEPTOR MUTANT INTERPRETED IN TERMS OF THE ALLOSTERIC MODEL

An extended Monod-Wyman-Changeux allosteric-type model is applied to h uman 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 t he 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-0 = [B-0]/[A(0)]. For wild-type receptors the model with L-0 = 9 x 10(8) provides a satisfactory representation of published pa tch-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 L-0 = 100 accounts for the trimodal distribution reported f or open-channel dwell times, with peaks at 0.15, 3.8 and 60 ms that co rrespond to non-, mono- and bi-liganded receptors, respectively. Possi ble applications of the allosteric model to other myasthenic mutants a re considered.