Inhibitory effects of dihydropyridines on macroscopic K⁺ currents and on the large-conductance Ca²⁺-activated K⁺ channel in cultured cerebellar granule cells

Abstract

In cultured cerebellar granule cells, we examined the effects of dihydropyridines (DHPs) on K⁺ currents, using the whole-cell recording configuration of the patch-clamp technique and on Ca²⁺-activated K⁺ channels (“maxi K⁺ channels”) using outside-out patches. We found that micromolar concentrations of nicardipine, nifedipine, (+) and (−) BAY K 8644, nitrendipine, nisoldipine and (−) nimodipine block 10–60% of macroscopic K⁺ currents. The most potent of these DHPs was nicardipine and the least potent, (−) BAY K 8644. (+) Nimodipine had no effect on this current. The inhibitory effects of nifedipine and nicardipine were not additive with those of 1 mM tetraethylammonium (TEA). Outside-out recordings of “maxi K⁺ channels” showed a main conductance of 200 pS (in 77% of the patches) and two subconductance states (in 23% of the patches). Neither nifedipine nor nicardipine affected the main conductance, but decreased the values of the subconductance levels. In 10% of these patches, nicardipine induced a flickering activity of the channel. These findings show that both Ca²⁺ and K⁺ channels have DHP-sensitive sites, suggesting similarity in electrostatic binding properties of these channels. Furthermore, cerebellar granule cells may express different subtypes of “maxi K⁺ channels” having different sensitivities to DHPs. These drugs may provide new tools for the molecular study of K⁺ channels.