Potentiation and inhibition of neuronal alpha 4 beta 4 nicotinic acetylcholine receptors by choline

The effects of choline on alpha 4 beta 4 nicotinic acetylcholine receptors, expressed in Xenopus oocytes, were investigated using the two-microelectro de voltage clamp technique. Particular attention was paid to the interactio n between the effects of acetylcholine and choline. Choline was a low-affin ity agonist of alpha 4 beta 4 receptors with an efficacy of 10% as compared to acetylcholine. Responses evoked by 1 mu M acetylcholine were potentiate d by low concentrations of choline and inhibited by > 10 mM choline, result ing in a bell-shaped concentration-effect relationship. Conversely. the eff ects of choline on responses evoked by 300 mu M acetylcholine resulted in a monophasic inhibition curve with an IC50 of 0.87 mM. The data were fitted by a two-site receptor occupation model, which accounts for similar effects of various cholinergic ligands on heteromeric nicotinic receptors. The res ults indicate that the potentiation was a competitive effect, whereas the i nhibition was due to a mixture of competitive and non-competitive effects. It is concluded that choline acts as a potent, endogenous co-agonist at het eromeric alpha 4 beta 4 nicotinic receptors. (C) 2000 Elsevier Science B.V. All rights reserved.