[Facilitatory actions of the cognitive enhancer nefiracetam on neuronal Ca2+ channels and nicotinic ACh receptors: their intracellular signal transduction pathways].
Nootropics are proposed to serve as cognition enhancers. The underlying mechanism, however, is largely unknown. We have attempted to assess the intracellular signal transduction pathways mediating the action of nefiracetam, a nootropic agent, on neuronal Ca2+ channels and nicotinic ACh receptors. In NG108-15 cells, nefiracetam (1 microM) enhanced the activities of N/L-type Ca2+ channels without affecting T-type The nefiracetam action was mimicked by dibutyryl cAMP (1 mM), or blocked by pertussis toxin (PTX), indicating that PTX-sensitive inhibitory G-proteins and cAMP-dependent pathways mediate the drug action. Nefiracetam also exerted a dose-dependent biphasic effect on Torpedo nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes, in which the drug 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 PTX-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. It is concluded that nefiracetam interacts with PKA and PKC pathways, which may explain a cellular mechanism for the action of cognitive enhancers.
Yoshii
M
M
Department of Neurophysiology, Tokyo Institute of Psychiatry, Japan.
Nishizaki
T
T
Watabe
S
S
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014981:Xenopus
D015220:Calcium Channels; D018697:Nootropic Agents; D011760:Pyrrolidinones; D011978:Receptors, Nicotinic; C058876:nefiracetam; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C