Nefiracetam Modulates Acetylcholine Receptor Currents via Two Different Signal Transduction Pathways

  1. Tomoyuki Nishizaki1,
  2. Toshiyuki Matsuoka1,
  3. Tamotsu Nomura1,
  4. Katumi Sumikawa2,
  5. Tadashi Shiotani3,
  6. Shigeo Watabe3 and
  7. Mitsunobu Yoshii4
  1. 1Department of Physiology, Kobe University School of Medicine, 7–5-1 Kusunoki-cho, Chuo-ku, Kobe 650, Japan (T.Ni., T.M., T. No.),2Department of Psychobiology, University of California, Irvine, CA 92717-4550 (K.S.), 3Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd., Kitakasai, Edogawa-ku, Tokyo 134, Japan (T.S., S.W.), and 4Department of Neurophysiology, Tokyo Institute of Psychiatry, 2–1-8 Kamikitazawa, Setagaya-ku, Tokyo 156, Japan (M.Y.)

    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 mutantTorpedo 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 μm) and a long-term enhancement of the currents at micromolar concentrations (1–10 μm). 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 Ca2+-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.

    Footnotes

    • Send reprint requests to: Dr. Tomoyuki Nishizaki, Department of Physiology, Kobe University School of Medicine, 7–5-1 kusunoki-cho, Chuo-ku, Kobe 650, Japan. E-mail:tomo{at}med.kobe-u.ac.jp

    • This work was supported in part by a research grant from the Muscular Dystrophy Association.

    • Abbreviations:
      nACh
      nicotinic acetylcholine
      ACh
      acetylcholine
      PKA
      cAMP-dependent protein kinase
      PKC
      protein kinase C
      HEPES
      4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
      EGTA
      ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
      [Ca2+]i, intracellular free calcium concentration
      PTX, pertussis toxin
      • Received August 19, 1997.
      • Accepted October 9, 1997.
    « Previous | Next Article »Table of Contents

    This Article

    1. Molecular Pharmacology January 1, 1998 vol. 53 no. 1 1-5
    1. » Abstract
    2. Full Text
    3. Full Text (PDF)

    Classifications

    Responses

    1. Submit a response
    2. No responses published

    Current Issue

    1. November 2009, 76 (5)
    1. Current Issue
    1. Alert me to new issues of Molecular Pharmacology