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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 29, 2005; DOI: 10.1124/jpet.105.093856

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Received for publication August 8, 2005.
Revised September 27, 2005.
Accepted for publication September 28, 2005.

Molecular mechanisms for BK channel activation by a novel opener, 12, 14-dichlorodehydroabietic acid

Kazuho Sakamoto 1, Taro Nonomura 2, Susumu Ohya 1, Katsuhiko Muraki 1, Tomohiko Ohwada 2, Yuji Imaizumi 1*

1 Dept. of Molecular and Cellular Pharmacol, Graduate School of Pharmaceutical Sci., Nagoya City Univ. 2 Lab. of Organic and Medicinal Chem., Graduate Scool of Pharmaceutical Sci., The Univ. of Tokyo

* Address correspondence to: E-mail: yimaizum{at}phar.nagoya-cu.ac.jp

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. We examined here, by using channel-expression system in HEK293 cells, the mechanisms underlying the BK channel opening action of diCl-DHAA and which subunit of BK channel ({alpha} or {beta}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{alpha} 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 significantly showed inversed voltage-dependence; larger potentiation at lower potentials. Since co-expression of {beta}1 subunit with BK{alpha} did not affect the potency of diCl-DHAA, the site of action for diCl-DHAA is suggested to be BK{alpha} subunit. Moreover, kinetic analysis of single channel currents indicates that diCl-DHAA opens BK{alpha} mainly by decreasing the time staying in a long closed state. Although reconstituted voltage-dependent Ca2+ channel current was significantly reduced by 1µM diCl-DHAA, BK channels were selectively activated at lower concentrations. These results indicate that diCl-DHAA is one of the most potent and selective BK channel openers acting on BK{alpha} and a useful proto-type compound to develop a novel BK channel opener.


Key words: BK channel, abietic acid, ion channel, opener, potassium channel, single channel current


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