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 (P _open) 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 P _open 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