Zwart_2000_Eur.J.Pharmacol_393_209

The effects of choline on alpha4beta4 nicotinic acetylcholine receptors, expressed in Xenopus oocytes, were investigated using in the two-microelectrode voltage clamp technique. Particular attention was paid to the interaction between the effects of acetylcholine and choline. Choline was a low-affinity agonist of alpha4beta4 receptors with an efficacy of 10% as compared to acetylcholine. Responses evoked by 1 microM acetylcholine were potentiated by low concentrations of choline and inhibited by > 10mM choline, resulting in a bell-shaped concentration-effect relationship. Conversely, the effects of choline on responses evoked by 300 microM acetylcholine resulted in a monophasic inhibition curve with an IC(50) 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 results indicate that the potentiation was a competitive effect, whereas the inhibition was due to a mixture of competitive and non-competitive effects. It is concluded that choline acts as a potent, endogenous co-agonist at heteromeric alpha4beta4 nicotinic receptors.