Kazuho Sakamoto, Taro Nonomura, S. Ohya
Jan 1, 2006
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Journal
Journal of Pharmacology and Experimental Therapeutics
Abstract
Our recent study has revealed that 12,14-dichlorodehydroabietic acid (diCl-DHAA), which is synthetically derived from a natural product, abietic acid, is a potent opener of large conductance Ca2+-activated K+ (BK) channel. Here, we examined, by using a channel expression system in human embryonic kidney 293 cells, the mechanisms underlying the BK channel opening action of diCl-DHAA and which subunit of the BK channel (α or β1) is the site of action for diCl-DHAA. BK channel activity was significantly enhanced by diCl-DHAA at concentrations of 0.1 μM and higher in a concentration-dependent manner. diCl-DHAA enhanced the activity of BKα by increasing sensitivity to both Ca2+ and membrane potential without changing the single channel conductance. It is notable that the increase in BK channel open probability by diCl-DHAA showed significant inverse voltage dependence, i.e., larger potentiation at lower potentials. Since coexpression of β1 subunit with BKα did not affect the potency of diCl-DHAA, the site of action for diCl-DHAA is suggested to be BKα subunit. Moreover, kinetic analysis of single channel currents indicates that diCl-DHAA opens BKα mainly by decreasing the time staying in a long closed state. Although reconstituted voltage-dependent Ca2+ channel current was significantly reduced by 1 μM diCl-DHAA, BK channels were selectively activated at lower concentrations. These results indicate that diCl-DHAA is one of the most potent BK channel openers acting on BKα and a useful prototype compound to develop a novel BK channel opener.