Modal gating of endplate acetylcholine receptors: A proposed mechanism

435 C o m m e n t a r y Decades ago as a beginning graduate student, one of us (K.L.M.) was studying short-term synaptic plasticity at the neuromuscular synapse. The responses were generally consistent from day to day, but there was some variability. At that time, K.L.M. naively thought that if it were possible to directly study the macromolecular building blocks underlying neuromuscular transmission , the variability would disappear. The advent of recording from single ion channels showed just how naive this wishful thinking was. Single-channel current records, which indicate the opening and closing transitions of a channel by step changes in the current, revealed that successive open-and closed-interval durations were sto-chastic in nature, with the interval durations ranging many orders of magnitude, and predictable only in terms of probabilities. In retrospect, such stochastic variation of single ion channel gating was predictable from the observed exponential decays of macroscopic ionic currents recorded from cells when large numbers of open channels were closing (Hodgkin and Huxley, 1952; Magleby and Stevens, 1972); the exponential decays arose from exponentially distributed effective open durations (burst durations). With further analysis, the stochastic variation in ion channel gating was found to be far more complex. Channels can gate in multiple open and closed kinetic states, with the mean lifetimes of the various kinetic states ranging over many orders of magnitude A further addition to variability was the observation at the single-channel level that channels can switch between different modes of gating for constant experimental conditions, with the duration of the gating in the various modes ranging from milliseconds to minutes (glutamate-activated channel, GluA3 receptor channels, Poon et al., 2011). Modal shifts in gating are typically identified by abrupt changes in mean open probability (Po), mean open-interval duration , and/or mean closed-interval duration. Whereas modal gating can be described by discrete-state Markov with shifts among different collections of kinetic states, the mechanism underlying modal gating has remained an enigma. This commentary now addresses a recent paper by Vij, Purohit, and Auerbach (Vij et al., 2015) that provides novel insight into the mechanism underlying modal gating for adult mouse endplate acetylcholine receptor (AChR) channels. Their study was possible in large part because they engineered a form of stable modal gating that could be readily studied. This is in contrast to the more typical transient modal gating identified by mode shifting, which can be difficult to study …