title: Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways.
abstract: Nootropic agents are proposed to serve as cognition enhancers. The underlying mechanism, however, is largely unknown. The present study was conducted to assess the intracellular signal transduction pathways mediated by the nootropic nefiracetam in the native and mutant Torpedo californica nicotinic acetylcholine (ACh) receptors expressed in Xenopus laevis oocytes. Nefiracetam induced a short-term depression of ACh-evoked currents at submicromolar concentrations (0.01-0.1 microM) and a long-term enhancement of the currents at micromolar concentrations (1-10 microM). The depression was caused by activation of pertussis toxin-sensitive, G protein-regulated, cAMP-dependent protein kinase (PKA) with subsequent phosphorylation of the ACh receptors; in contrast, the enhancement was caused by activation of Ca(2+)-dependent protein kinase C (PKC) and the ensuing PKC phosphorylation of the receptors. Therefore, nefiracetam interacts with PKA and PKC pathways, which may explain a cellular mechanism for the action of cognition-enhancing agents.
authors.affiliation: Department of Physiology, Kobe University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nishizaki
authors.forename: T
authors.initials: T
authors.lastname: Matsuoka
authors.forename: T
authors.initials: T
authors.lastname: Nomura
authors.forename: K
authors.initials: K
authors.lastname: Sumikawa
authors.forename: T
authors.initials: T
authors.lastname: Shiotani
authors.forename: S
authors.initials: S
authors.lastname: Watabe
authors.forename: M
authors.initials: M
authors.lastname: Yoshii
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology*; D009865:Oocytes / Q000502:physiology / Q000648:ultrastructure; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D014101:Torpedo; D014981:Xenopus
chemical_list: D018697:Nootropic Agents; D011760:Pyrrolidinones; D011950:Receptors, Cholinergic; C058876:nefiracetam; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C