Type I and II positive allosteric modulators differentially modulate agonist-induced up-regulation of α7 nicotinic acetylcholine receptors

J Neurochem. 2012 Oct;123(1):73-83. doi: 10.1111/j.1471-4159.2012.07876.x. Epub 2012 Aug 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Analysis of Variance
  • Animals
  • Autoradiography
  • Brain / anatomy & histology
  • Brain / drug effects
  • Brain / metabolism
  • Bungarotoxins / metabolism
  • Cholinergic Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Iodine Isotopes / pharmacology
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Nicotine / pharmacology
  • Protein Binding / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, Nicotinic / physiology*
  • Transfection
  • Up-Regulation / drug effects*
  • alpha7 Nicotinic Acetylcholine Receptor


  • Bungarotoxins
  • Cholinergic Agents
  • Chrna7 protein, human
  • Chrna7 protein, rat
  • Iodine Isotopes
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • Nicotine
  • L-Lactate Dehydrogenase