title: Exploring the positive allosteric modulation of human α7 nicotinic receptors from a single-channel perspective.
abstract: 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.
authors.affiliation: Universidad Nacional del Sur/CONICET, Instituto de Investigaciones Bioquímicas de Bahía Blanca, Bahía Blanca 8000, Argentina.
authors.forename: Natalia D
authors.initials: ND
authors.lastname: Andersen
authors.affiliation: Universidad Nacional del Sur/CONICET, Instituto de Investigaciones Bioquímicas de Bahía Blanca, Bahía Blanca 8000, Argentina.
authors.forename: Beatriz E
authors.initials: BE
authors.lastname: Nielsen
authors.affiliation: Universidad Nacional del Sur/CONICET, Instituto de Investigaciones Bioquímicas de Bahía Blanca, Bahía Blanca 8000, Argentina.
authors.forename: Jeremías
authors.initials: J
authors.lastname: Corradi
authors.affiliation: Universidad Nacional del Sur/CONICET, Instituto de Investigaciones Bioquímicas de Bahía Blanca, Bahía Blanca 8000, Argentina.
authors.forename: María F
authors.initials: MF
authors.lastname: Tolosa
authors.affiliation: Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.affiliation: Department of Medical Education, California Northstate University College of Medicine, Elk Grove, CA 95757, USA.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Arias
authors.affiliation: Universidad Nacional del Sur/CONICET, Instituto de Investigaciones Bioquímicas de Bahía Blanca, Bahía Blanca 8000, Argentina. Electronic address: inbouzat@criba.edu.ar.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bouzat
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D002460:Cell Line; D018678:Cholinergic Agents / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D009154:Mutation; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D013696:Temperature; D014162:Transfection; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D002413:Cations, Divalent; D018678:Cholinergic Agents; D007555:Isoxazoles; D010671:Phenylurea Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002118:Calcium
keywords: Cys-loop receptors; Nicotinic receptors; Patch-clamp; Positive allosteric modulators; Single-channel recordings