1. Type I and II positive allosteric modulators differentially modulate agonist-induced up-regulation of α7 nicotinic acetylcholine receptors.
- Author
-
Thomsen MS and Mikkelsen JD
- Subjects
- Allosteric Regulation drug effects, Analysis of Variance, Animals, Autoradiography, Brain anatomy & histology, Brain drug effects, Brain metabolism, Bungarotoxins metabolism, Dose-Response Relationship, Drug, Iodine Isotopes pharmacology, L-Lactate Dehydrogenase metabolism, Male, Nicotine pharmacology, Protein Binding drug effects, Rats, Rats, Wistar, Transfection, alpha7 Nicotinic Acetylcholine Receptor, Cholinergic Agents pharmacology, Receptors, Nicotinic physiology, Up-Regulation drug effects
- Abstract
Long-term treatment with nicotine or selective α7 nicotinic acetylcholine receptor (nAChR) agonists increases the number of α7 nAChRs and this up-regulation may be involved in the mechanism underlying the sustained procognitive effect of these compounds. Here, we investigate the influence of type I and II α7 nAChR positive allosteric modulators (PAMs) on agonist-induced α7 nAChR up-regulation. We show that the type II PAMs, PNU-120596 (10 μM) or TQS (1 and 10 μM), inhibit up-regulation, as measured by protein levels, induced by the α7 nAChR agonist A-582941 (10 nM or 10 μM), in SH-EP1 cells stably expressing human α7 nAChR, whereas the type I PAMs AVL-3288 or NS1738 do not. Contrarily, neither type I nor II PAMs affect 10 μM nicotine-induced receptor up-regulation, suggesting that nicotine and A-582941 induce up-regulation through different mechanisms. We further show in vivo that 3 mg/kg PNU-120596 inhibits up-regulation of the α7 nAChR induced by 10 mg/kg A-582941, as measured by [(125)I]-bungarotoxin autoradiography, whereas 1 mg/kg AVL-3288 does not. Given that type II PAMs decrease desensitization of the receptor, whereas type I PAMs do not, these results suggest that receptor desensitization is involved in A-582941-induced up-regulation. Our results are the first to show an in vivo difference between type I and II α7 nAChR PAMs, and demonstrate an agonist-dependent effect of type II PAMs occurring on a much longer time scale than previously appreciated. Furthermore, our data suggest that nicotine and A-582941 induce up-regulation through different mechanisms, and that this confers differential sensitivity to the effects of α7 nAChR PAMs. These results may have implications for the clinical development of α7 nAChR PAMs., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)
- Published
- 2012
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