Potentiation of the Human α7 Acetylcholine Receptor: A Single-Channel Study

Allosteric modulation of neuronal nicotinic acetylcholine receptors by exogenous ligands is a promising strategy for the treatment of several neurological disorders including Alzheimer's disease and Schizophrenia. To gain insight into the molecular mechanisms underlying allosteric modulation, we have examined with single-channel recordings, the potentiation of human α7 nicotinic acetylcholine receptors by both a Type I, and a Type II positive allosteric modulator (PAM). Dwell time analysis reveals that both NS-1738 (Type I PAM) and PNU-120596 (PNU; Type II PAM) lead to prolonged openings in the presence of agonist. While co-application of NS-1738 with agonist results in the appearance of a single new component in open time histograms, co-application of PNU leads to two additional components, the longest of which coalesce into clusters of openings whose frequency and duration depend on PNU concentration. At saturating concentrations of PNU these clusters last as long as several minutes, representing a ∼10,000-100,000 fold prolongation of the notoriously brief α7 openings. The differences between Type I and Type II potentiation evident at the microscopic/single-channel level will be discussed in the context of the variable phenotypes previously characterized at the macroscopic/whole cell level.View Large Image | View Hi-Res Image | Download PowerPoint Slide