Multiple components in the agonist concentration-response relationships ofneuronal nicotinic acetylcholine receptors

Assessing the potential of nicotinic agonists as therapeutic agents has fre quently relied upon single component EC50 values obtained from studies of n icotinic receptors expressed in Xenopus oocytes. We have evaluated the vali dity of this approach using voltage clamp techniques. In general, agonist c oncentration - response plots for the alpha 3 beta 2, alpha 3 beta 4, alpha 4-1 beta 2, alpha 4-1 beta 4 and alpha 7 combinations were poorly fitted b y a single component Hill-equation. Improved fits were obtained with the su m of two components, although only in the case of alpha 3 beta 4 and alpha 4-1 beta 2 was the improvement significant regardless of the weighting meth od used. For the acetylcholine (ACh) concentration-response relationships o f the alpha 4-1 beta 2 combination, the two EC50 values were 0.3 and 58.3 m u M. For the alpha 3 beta 4 combination, the two EC50 components were 39 an d 2919 mu M. The 39 mu M component of alpha 3 beta 4 represented 36% of the sum of the maximum responses of both curves. This shows that for some comb inations, the secondary components represent a well-separated, major popula tion of receptors. Therefore, published EC50 values which assume that only a single subtype of functional receptor is present may not accurately descr ibe agonist action may therefore need to be re-evaluated. (C) 2000 Elsevier Science B.V. All rights reserved.