The neuronal nicotinic α4β2 receptor has a high maximal probability of being open

Background and purpose: A fundamental property of transmitter-gated ion channels is the probability a channel will be open (Popen) when stimulated by a concentration of agonist that elicits a maximal response. This value is critical for interpreting steady-state concentration–response relationships in terms of channel activation, and for understanding the actions of drugs that potentiate responses. We used analysis of non-stationary noise to estimate the maximal probability the nicotinic α4β2 receptor is open. Experimental approach: HEK293 cells stably transfected to express human α4β2 nicotinic receptors were studied using whole-cell voltage clamp. Nicotinic agonists (acetylcholine, nicotine, cytisine and 5-iodo A-85380) were applied, and the relationship between variance of the elicited whole-cell current and mean current was analysed. Key results: The variance did not increase linearly with the mean current. For acetylcholine and nicotine the relationship between variance and mean indicates that the maximal Popen is greater than 0.8. The number of agonist-activatable channels was estimated to be about 1000 per cell. The mean single channel conductance at −60 mV was indistinguishable when currents were elicited by acetylcholine (18 pS), nicotine (17 pS) or 5-iodo A-85380 (17 pS), whereas the value for cytisine was larger (24 pS). Conclusions and implications: The neuronal nicotinic α4β2 receptor has a maximal probability of being open that is greater than 0.8. This conclusion applies to the receptor containing three α4 and two β2 subunits (the low-sensitivity stoichiometry), but may not apply to the receptor containing two α4 and three β2 subunits (the high-sensitivity stoichiometry). This article is commented on by Papke, pp. 1903–1905 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00868.x