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

Assessing the potential of nicotinic agonists as therapeutic agents has frequently relied upon single component EC50 values obtained from studies of nicotinic receptors expressed in Xenopus oocytes. We have evaluated the validity of this approach using voltage clamp techniques. In general, agonist concentration - 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 by a single component Hill-equation. Improved fits were obtained with the sum 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 method used. For the acetylcholine (ACh) concentration-response relationships of the alpha 4-1 beta 2 combination, the two EC50 values were 0.3 and 58.3 mu M. For the alpha 3 beta 4 combination, the two EC50 components were 39 and 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 combinations, the secondary components represent a well-separated, major population of receptors. Therefore, published EC50 values which assume that only a single subtype of functional receptor is present may not accurately describe agonist action may therefore need to be re-evaluated. (C) 2000 Elsevier Science B.V. All rights reserved.