Potentiation and inhibition of neuronal alpha4beta4 nicotinic acetylcholine receptors by choline.
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.
Zwart
R
R
Research Institute of Toxicology, Utrecht University, PO Box 80.176, NL-3508 TD, Utrecht, Netherlands. r.zwart@ritox.vet.uu.nl
Vijverberg
H P
HP
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002794:Choline / Q000494:pharmacology*; D004357:Drug Synergism; D004594:Electrophysiology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009865:Oocytes; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D002794:Choline; D000109:Acetylcholine