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- a nd 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 acety lcholine (ACh), respectively. Concentration-response relationships for ACh were examined in the presence and absence of cytisine. Although c ytisine was relatively ineffective in stimulating current, the coappli cation of cytisine and ACh reduced the responses to ACh. For alpha 4 b eta 2 receptors, 3 mu M cytisine shifted the dose-response curve for A Ch to the right, resulting in a 60-fold increase in the apparent EC(50 ) for ACh. For alpha 3 beta 2 receptors, 30 mu M cytisine shifted the apparent EC(50) for ACh from approximate to 150 mu M to 1 mM. Although the efficacy of cytisine for alpha 3 beta 2 receptors was very low, c ytisine could effectively inhibit the responses of these receptors, wi th an IC50 of approximate to 10 mu M. The efficacy of cytisine for alp ha 4 beta 2 receptors was greater than that for alpha 3 beta 2 recepto rs, and it was possible to evaluate the partial agonist properties of cytisine for these receptors. Although the EC(50) of cytisine for stim ulating current through alpha 4 beta 2 receptors was about 1 mu M, con centrations of cytisine as low as 20 nM were able to inhibit 50% of th e response to 1 mu M ACh. The inhibitory effects of cytisine were reve rsible 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 competit ive 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 effi cacy of cytisine are relatively low.