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CELLULAR AND MOLECULAR

Molecular Mechanisms for Large Conductance Ca²⁺-Activated K⁺ Channel Activation by a Novel Opener, 12,14-Dichlorodehydroabietic Acid

Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.S., S.O., K.M., Y.I.); and Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (T.N., T.O.)

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 ( or 1) 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 BK 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 1 subunit with BK did not affect the potency of diCl-DHAA, the site of action for diCl-DHAA is suggested to be BK subunit. Moreover, kinetic analysis of single channel currents indicates that diCl-DHAA opens BK 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 BK and a useful prototype compound to develop a novel BK channel opener.

Address correspondence to: Dr. Yuji Imaizumi, Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabedori, Mizuhoku, Nagoya 467-8603, Japan. E-mail: yimaizum{at}phar.nagoya-cu.ac.jp

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