PT - JOURNAL ARTICLE AU - Kazuho Sakamoto AU - Taro Nonomura AU - Susumu Ohya AU - Katsuhiko Muraki AU - Tomohiko Ohwada AU - Yuji Imaizumi TI - Molecular Mechanisms for Large Conductance Ca<sup>2+</sup>-Activated K<sup>+</sup> Channel Activation by a Novel Opener, 12,14-Dichlorodehydroabietic Acid AID - 10.1124/jpet.105.093856 DP - 2006 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 144--153 VI - 316 IP - 1 4099 - http://jpet.aspetjournals.org/content/316/1/144.short 4100 - http://jpet.aspetjournals.org/content/316/1/144.full SO - J Pharmacol Exp Ther2006 Jan 01; 316 AB - 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. The American Society for Pharmacology and Experimental Therapeutics