Menthol blocks dihydropyridine‐insensitive Ca2+ channels and induces neurite outgrowth in human neuroblastoma cells

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Abstract
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 to 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 and menthol suggests a role for certain types of Ca2+ channels in triggering growth and morphologic changes in LA-N-5 cells.