Study on enhancement of neuronal calcium channel activities by nootropic agents

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Effects of nootropic agents (pyrrolidone derivatives) on neuronal calcium (Ca) channels were studied in NG108-15 cells using the whole-cell patch-clamp technique. Nefiracetam (DM-9384), a newly-developed nootropic agent, increased a high voltage-activated, long-lasting component of Ca channel currents two-fold at a low concentration of 1muM without affecting a low voltage-activated, transient component. The dose-response relationship yielded a bell-shaped curve with a peak at 1 muM.Similar, but less potent effects were observed by other nootropic agents in the sequence of nefiracetam > aniracetam > oxiracetam > piracetam. Dibutyryl cyclic AMP (1 mM), an analogue of cyclic AMP, also enhanced the currents, which were not further increased by nefiracetam, or vice versa. The currents enhanced by nefiracetam were markedly reduced by nifedipine (10 muM), an L-type Ca channel blocker. The remaining N-type currents also showed a slightly increase (up to 1.5-fold). These facilitatory actions of nefiracetam were prevented by the non-specific protein kinase inhibitor, H-7 (100 muM). Cells treated with pertussis toxin (500 ng/ml, >20 h) to inactivate inhibitory G-proteins (Go/Gi) were apparently insensitive to nefiracetam. The results suggest that the nootropic agents may enhance the activity of neuronal L-type Ca channels under the regulation of inhibitory G-proteins and possibly, cyclic AMP-dependent processes.