Partial agonist properties of cytisine on neuronal nicotinic receptors containing the beta 2 subunit

As previously reported by Luetje and Patrick [J. Neurosci. 11:837-845 (1991)], the nicotine-like alkaloid cytisine is relatively ineffective in evoking current responses from nicotinic receptors containing the beta 2 subunit. In our experiments, the responses of alpha 4 beta 2- and alpha 3 beta 2-injected oocytes to the application of 1 mM cytisine were only 14.7 +/- 4% and 2.5 +/- 0.8% of the responses to 1 mM acetylcholine (ACh), respectively. Concentration-response relationships for ACh were examined in the presence and absence of cytisine. Although cytisine was relatively ineffective in stimulating current, the coapplication of cytisine and ACh reduced the responses to ACh. For alpha 4 beta 2 receptors, 3 microM cytisine shifted the dose-response curve for ACh to the right, resulting in a 60-fold increase in the apparent EC50 for ACh. For alpha 3 beta 2 receptors, 30 microM cytisine shifted the apparent EC50 for ACh from approximately 150 microM to 1 mM. Although the efficacy of cytisine for alpha 3 beta 2 receptors was very low, cytisine could effectively inhibit the responses of these receptors, with an IC50 of approximately 10 microM. The efficacy of cytisine for alpha 4 beta 2 receptors was greater than that for alpha 3 beta 2 receptors, and it was possible to evaluate the partial agonist properties of cytisine for these receptors. Although the EC50 of cytisine for stimulating current through alpha 4 beta 2 receptors was about 1 microM, concentrations of cytisine as low as 20 nM were able to inhibit 50% of the response to 1 microM ACh. The inhibitory effects of cytisine were reversible over a period of 5 min. Our analysis suggests that cytisine is a true partial agonist for beta 2-containing ACh receptors and as such can inhibit the response of these receptors to ACh through a competitive mechanism. In the case of alpha 4 beta 2 receptors cytisine binds with high apparent affinity and low efficacy to a site shared with ACh, and for alpha 3 beta 2 receptors both the apparent affinity and efficacy of cytisine are relatively low.