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Voltage-Sensitive Oxonol Dyes Are Novel Large-Conductance Ca²⁺-Activated K⁺ Channel Activators Selective for 1 and 4 but Not for 2 Subunits

Department of Molecular & Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (T.M., K.S., H.S., S.O., Y.I.); and Cell Signaling & Ion Channel Research Group, Cellular Pharmacology, School of Pharmacy, Aichigakuin University, Nagoya, Japan (K.M.)

The large-conductance Ca²⁺-activated K⁺ (BK) channel is activated by both the increase of intracellular Ca²⁺ concentration and membrane depolarization. The BK channel plays crucial roles as a key molecule in the negative feedback mechanism regulating membrane excitability and cellular Ca²⁺ in various cell types. Here, we report that a widely used slow-response voltage-sensitive fluorescent dye, bis(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC₄(3)], is a potent BK channel activator. The application of DiBAC₄(3) at concentrations of 10 nM and higher significantly increased whole-cell BK channel currents in human embryonic kidney 293 cells expressing rat BK channel and 1 subunits (rBK1). In the presence of 300 nM DiBAC₄(3), the activation voltage of the BK channel current shifted to the negative direction by approximately 30 mV, but the single-channel conductance was not affected. DiBAC₄(3) activated whole-cell rBK1 and rBK4 currents in the same concentration range but partially blocked rBK2 currents. The BK channel subunit alone and some other types of K⁺ channels examined were not markedly affected by 1 µM DiBAC₄(3). Structure-activity relationship analyses revealed that a set of oxo- and oxoanion-moieties in two 1,3-dialkylbarbituric acids, which are conjugated by oligomethine, is the novel skeleton for the -subunit-selective BK channel-opening property of DiBAC₄(3) and related oxonol compounds. This conjugated structure may be located stereochemically in one plane. These findings provide a molecular and structural basis for understanding the regulatory mechanism of BK channel activity by an auxiliary subunit and will be fundamental to the development of -selective BK channel openers.

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. E-Mail: yimaizum{at}phar.nagoya-cu.ac.jp

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