Menthol blocks dihydropyridine-insensitive Ca2+ channels and induces neurite outgrowth in human neuroblastoma cells.
Voltage-gated Ca2+ channels were identified in LA-N-5 human neuroblastoma cells using the Ca2+ sensitive fluorescent probe, fura-2. Using a variety of "classical" Ca2+ channel blockers, we have demonstrated the presence of both dihydropyridine (DHP)-sensitive and -insensitive channel types that can be activated by depolarization of the cells with either high K+ or gramicidin in the bathing solution. Brief exposure of LA-N-5 cells to menthol blunted the depolarization-induced Ca2+ influx though both DHP-sensitive and DHP-insensitive channels. This effect is concentration dependent (50% maximal blocking effect with 0.25 mM menthol), rapid in onset, and readily reversible. The specificity of the Ca2(+)-channel blocking effect of menthol was demonstrated in parallel studies using compounds with similar structures: menthone blocked Ca2+ channels with about half the potency of menthol, while cyclohexanol was without effect. Addition of either menthol or menthone to LA-N-5 cultures induced neurite outgrowth, cellular clustering, and reduction of cell growth in a dose-dependent fashion that correlated with the ability of these compounds to inhibit the DHP-insensitive Ca2+ influx. Cyclohexanol had no biologic activity. Taken together, the parallel potency for blockade of DHP-insensitive Ca2+ influx with the biologic activity of menthol suggests a role for certain types of Ca2+ channels in triggering growth and morphologic changes in LA-N-5 cells.
Sidell
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Division of Neuropathology, UCLA School of Medicine 90024.
Verity
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Nord
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D000110:Acetylcholinesterase / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D001572:Benzofurans; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D003511:Cyclohexanols / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D005456:Fluorescent Dyes; D016257:Fura-2; D006801:Humans; D008610:Menthol / Q000494:pharmacology*; D009447:Neuroblastoma / Q000503:physiopathology* / Q000648:ultrastructure; D013729:Terpenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D001572:Benzofurans; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003511:Cyclohexanols; D004095:Dihydropyridines; D005456:Fluorescent Dyes; D013729:Terpenes; D008610:Menthol; C038806:1,4-dihydropyridine; C019466:menthone; D000110:Acetylcholinesterase; D002118:Calcium; D016257:Fura-2