Cellular mechanism of action of cognitive enhancers: effects of nefiracetam on neuronal Ca2+ channels.
Cellular mechanisms underlying the cognition-enhancing actions of piracetam-like nootropics were studied by recording Ca2+ channel currents from neuroblastoma x glioma hybrid (NG108-15) cells and Xenopus oocytes expressing Ca2+ channels. In NG108-15 cells, nefiracetam (1 microM) produced a twofold increase in L-type Ca2+ channel currents. A similar, but slightly less potent effect was observed with aniracetam, whereas piracetam and oxiracetam exerted no such effects. Cyclic AMP analogs mimicked the nefiracetam action. N-type Ca2+ channel currents inhibited by leucine (Leu)-enkephalin by means of inhibitory G proteins (Go/Gi) were recovered promptly by nefiracetam, whereas those inhibited by prostaglandin E1 via stimulatory G proteins were not affected by nefiracetam. Cells treated with pertussis toxin (500 ng/mL, > 20 hours) were insensitive to nefiracetam. In Xenopus oocytes functionally expressing N-type (alpha1B) Ca2+ channels and delta-opioid receptors, nefiracetam was also effective in facilitating the recovery from Leu-enkephalin-induced inhibition. These results suggest that nefiracetam, and possibly aniracetam, may activate N- and L-type Ca2+ channels in a differential way depending on how they recover from Go/Gi-mediated inhibition.
Yoshii
M
M
Department of Neurophysiology, Tokyo Institute of Psychiatry, Japan.
Watabe
S
S
Murashima
Y L
YL
Nukada
T
T
Shiotani
T
T
D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D020864:Calcium Channels, N-Type / Q000187:drug effects* / Q000502:physiology; D003071:Cognition / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005910:Glioma; D006801:Humans; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects; D018697:Nootropic Agents / Q000494:pharmacology*; D009865:Oocytes; D011760:Pyrrolidinones / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014981:Xenopus
D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D018697:Nootropic Agents; D011760:Pyrrolidinones; C058876:nefiracetam; D000242:Cyclic AMP; D019204:GTP-Binding Proteins