NEFIRACETAM MODULATES ACETYLCHOLINE-RECEPTOR CURRENTS VIA 2 DIFFERENTSIGNAL-TRANSDUCTION PATHWAYS

Nootropic agents are proposed to serve as cognition enhancers. The und erlying mechanism, however, is largely unknown, The present study was conducted to assess the intracellular signal transduction pathways med iated by the nootropic nefiracetam in the native and mutant Torpedo ca lifornica nicotinic acetylcholine (ACh) receptors expressed in Xenopus laevis oocytes. Nefiracetam induced a short-term depression of ACh-ev oked currents at submicromolar concentrations (0.01-0.1 mu M) and a lo ng-term enhancement of the currents at micromolar concentrations (1-10 mu M). The depression was caused by activation of pertussis toxin-sen sitive, G protein-regulated, cAMP-dependent protein kinase (PKA) with subsequent phosphorylation of the ACh receptors; in contrast, the enha ncement was caused by activation of Ca2+-dependent protein kinase C (P KC) and the ensuing PKC phosphorylation of the receptors. Therefore, n efiracetam interacts with PKA and PKC pathways, which may explain a ce llular mechanism for the action of cognition-enhancing agents.