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(Circulation. 2005;111:198-203.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Mitochondrial Ca²⁺-Activated K⁺ Channels in Cardiac Myocytes

A Mechanism of the Cardioprotective Effect and Modulation by Protein Kinase A

From the Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan.

Correspondence to Toshiaki Sato, MD, PhD, Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail tsato{at}faculty.chiba-u.jp

Received July 5, 2004; revision received August 30, 2004; accepted October 15, 2004.

Background— The large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel in the cardiac inner mitochondrial membrane (mitoK_Ca channel) has been shown to protect the heart against ischemic injury. However, questions about the cardioprotective mechanism and the kinase-mediated regulation of mitoK_Ca channels remain to be answered.

Methods and Results— Flavoprotein fluorescence in guinea pig ventricular myocytes was measured to assay mitoK_Ca channel activity. The mitochondrial Ca²⁺ concentration ([Ca²⁺]_m) and membrane potential (_m) were measured by loading cells with rhod-2 and JC-1, respectively. Cell death was assessed by trypan blue permeability. The BK_Ca channel opener NS1619 reversibly increased the flavoprotein oxidation in a concentration-dependent manner. NS1619 (30 µmol/L) attenuated the ouabain (1 mmol/L)-induced elevation of [Ca²⁺]_m with accompanying depolarization of _m. These effects of NS1619 were completely antagonized by the BK_Ca channel blocker paxilline (2 µmol/L) but not by the mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channel blocker 5-hydroxydecanoate (500 µmol/L). Paxilline, however, failed to block the oxidative effect of diazoxide (100 µmol/L), a mitoK_ATP channel opener. The combined application of submaximally effective concentrations of NS1619 (10 µmol/L) and diazoxide (30 µmol/L) produced additive effects. NS1619 (30 µmol/L) blunted the rate of cell death during exposure to ouabain; this cardioprotective effect was prevented by paxilline. Activation of cAMP-dependent protein kinase by 8-bromoadenosine 3'5'-cyclic monophosphate (0.5 mmol/L) and forskolin (10 µmol/L) potentiated the NS1619-induced flavoprotein oxidation.

Conclusions— Opening of mitoK_Ca channels, which is modulated by cAMP-dependent protein kinase, depolarizes the _m and attenuates the mitochondrial Ca²⁺ overload. Our study further indicates that mitoK_Ca channel activation confers cardioprotection in a manner similar to but independent of mitoK_ATP channel activation.

Key Words: potassium channels, calcium-activated • myocytes • mitochondria • cyclic AMP-dependent protein kinases

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