Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective

Neuropharmacology. 2016 Aug:107:189-200. doi: 10.1016/j.neuropharm.2016.02.032. Epub 2016 Feb 27.


Enhancement of α7 nicotinic receptor (nAChR) function by positive allosteric modulators (PAMs) is a promising therapeutic strategy to improve cognitive deficits. PAMs have been classified only on the basis of their macroscopic effects as type I, which only enhance agonist-induced currents, and type II, which also decrease desensitization and reactivate desensitized nAChRs. To decipher the molecular basis underlying these distinct activities, we explored the effects on single-α7 channel currents of representative members of each type and of less characterized compounds. Our results reveal that all PAMs enhance open-channel lifetime and produce episodes of successive openings, thus indicating that both types affect α7 kinetics. Different PAM types show different sensitivity to temperature, suggesting different mechanisms of potentiation. By using a mutant α7 receptor that is insensitive to the prototype type II PAM (PNU-120596), we show that some though not all type I PAMs share the structural determinants of potentiation. Overall, our study provides novel information on α7 potentiation, which is key to the ongoing development of therapeutic compounds.

Keywords: Cys-loop receptors; Nicotinic receptors; Patch-clamp; Positive allosteric modulators; Single-channel recordings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Calcium / metabolism
  • Cations, Divalent / metabolism
  • Cell Line
  • Cholinergic Agents / pharmacology*
  • Humans
  • Isoxazoles / pharmacology
  • Kinetics
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Models, Molecular
  • Mutation
  • Patch-Clamp Techniques
  • Phenylurea Compounds / pharmacology
  • Protein Conformation
  • Rats
  • Temperature
  • Transfection
  • alpha7 Nicotinic Acetylcholine Receptor / agonists
  • alpha7 Nicotinic Acetylcholine Receptor / genetics
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*


  • 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea
  • Cations, Divalent
  • Cholinergic Agents
  • Isoxazoles
  • Phenylurea Compounds
  • alpha7 Nicotinic Acetylcholine Receptor
  • Calcium