In praise of single channel kinetics

The Rockefeller University Press $30.00 J. Gen. Physiol. 2016 Vol. 148 No. 2 79–88 www.jgp.org/cgi/doi/10.1085/jgp.201611649 79 It is more than 30 years since the advent of the gigaohm seal patch clamp technique, which enabled routine recordings of currents generated by the activity of a single ion channel molecule in its native environment. The muscle nicotinic acetylcholine (ACh) receptor (nAChR) is one of the best ligand-gated channels for single channel recording because of its sizable conductance, robust expression, and consistent subunit composition, both at the native neuromuscular junction and in heterologous expression systems. A specific application of single channel recording is kinetic analysis, the purpose of which is to understand how a channel activates in response to an appropriate stimulus. In a recent issue of The Journal of General Physiology, Mukhtasimova et al. report on their kinetic analysis of nAChR recordings at substantially improved temporal resolution. We shall discuss the implications of this achievement for our knowledge of how these ligand-gated channels work. In brief, the major findings confirm that there is a short-lived preopening conformation of the receptor, followed by the actual opening, and that partial agonists are partial because of a deficiency in the earlier preopening step.