Comparative pharmacology of rat and human α7 nAChR conducted with net charge analysis

I Pharmacological studies of alpha7 nicotinic acetylcholine receptors are confounded by the fact that rapid desensitization to high agonist concentration causes alpha7 peak responses to occur well in advance of complete solution exchange. For this reason, peak currents are an invalid measure of response to applied agonist concentrations. We show that results comparable to those that have been corrected for instantaneous concentration are obtained if net charge is used as the measure of receptor response. 2 Dose response curves obtained with these methods indicate that alpha7 receptors are approximately 10 fold more sensitive to agonist than previously reported. The agonists, ACh, choline, cytisine, GTS-21, 4OH-GTS-21 and 4-MeO-CA have the same rank order potency for both human and rat receptors: 4-MeO-CA > 4OH-GTS-21 > GTS-21 > cytisine > ACh > choline. However, differences in efficacy exist between rat and human receptors. GTS-21 is more efficacious for rat than human alpha7 receptors and cytisine more efficacious for human than rat alpha7 receptors. 3 Choline is the least potent agonist for both human and rat alpha7, with a potency approximately 10 fold lower than that of ACh. While the EC50 for the activation of alpha7 receptors by choline (400500 muM) is outside the normal physiological range (10-100 muM), choline can nonetheless produce detectable levels of channel activation in the physiological concentration range. Since these concentrations are relatively non-desensitizing, the contribution of choline-activated alpha7 receptor current may play a significant role in the regulation of calcium homeostasis in alpha7-expressing neurons.