Vol. 53, Issue 1, 1-5, January 1998

ACCELERATED COMMUNICATION
Nefiracetam Modulates Acetylcholine Receptor Currents via Two Different Signal Transduction Pathways

Tomoyuki Nishizaki, Toshiyuki Matsuoka, Tamotsu Nomura, Katumi Sumikawa, Tadashi Shiotani, Shigeo Watabe and Mitsunobu Yoshii

Department of Physiology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650, Japan (T.Ni., T.M., T. No.), Department of Psychobiology, University of California, Irvine, CA 92717-4550 (K.S.), Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd., Kitakasai, Edogawa-ku, Tokyo 134, Japan (T.S., S.W.), and Department of Neurophysiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156, Japan (M.Y.)

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 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.