Modulation of Mitochondrial ATP-Dependent K⁺ Channels by Protein Kinase C

From the Section of Molecular and Cellular Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Md.

Correspondence to Eduardo Marbán, MD, PhD, Section of Molecular and Cellular Cardiology, Department of Medicine, Johns Hopkins University, Ross 844/720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}welchlink.welch.jhu.edu

Abstract—Pharmacological openers of mitochondrial ATP-dependent K⁺ (mitoK_ATP) channels mimic ischemic preconditioning, and such cardioprotection can be prevented by mitoK_ATP channel blockers. It is also known that protein kinase C (PKC) plays a key role in the induction and maintenance of preconditioning. To look for possible mechanistic links between these 2 sets of observations, we measured mitochondrial matrix redox potential as an index of mitoK_ATP channel activity in rabbit ventricular myocytes. The mitoK_ATP channel opener diazoxide (100 µmol/L) partially oxidized the matrix redox potential. Exposure to phorbol 12-myristate 13-acetate (PMA, 100 nmol/L) potentiated and accelerated the effect of diazoxide. These effects of PMA were blocked by the mitoK_ATP channel blocker 5-hydroxydecanoate, which we verified to be a selective blocker of the mitoK_ATP channel in simultaneous recordings of membrane current and flavoprotein fluorescence. The inactive control compound 4-phorbol (100 nmol/L) did not alter the effects of diazoxide. We conclude that the activity of mitoK_ATP channels can be regulated by PKC in intact heart cells. Potentiation of mitoK_ATP channel opening by PKC provides a direct mechanistic link between the signal transduction of ischemic preconditioning and pharmacological cardioprotection targeted at ATP-dependent K⁺ channels.

Key Words: diazoxide • preconditioning • protein kinase C • mitochondria • 5-hydroxydecanoate

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				J. Seharaseyon, N. Sasaki, A. Ohler, T. Sato, H. Fraser, D. C. Johns, B. O'Rourke, and E. Marban Evidence against Functional Heteromultimerization of the KATP Channel Subunits Kir6.1 and Kir6.2 J. Biol. Chem., June 2, 2000; 275(23): 17561 - 17565. [Abstract] [Full Text] [PDF]

				T. Sato, N. Sasaki, J. Seharaseyon, B. O'Rourke, and E. Marban Selective Pharmacological Agents Implicate Mitochondrial but Not Sarcolemmal KATP Channels in Ischemic Cardioprotection Circulation, May 23, 2000; 101(20): 2418 - 2423. [Abstract] [Full Text] [PDF]

				E. J. Griffiths Mitochondria -- potential role in cell life and death Cardiovasc Res, April 1, 2000; 46(1): 24 - 27. [Full Text] [PDF]

				T. L. V. Hoek, L. B. Becker, Z.-H. Shao, C.-Q. Li, and P. T. Schumacker Preconditioning in Cardiomyocytes Protects by Attenuating Oxidant Stress at Reperfusion Circ. Res., March 17, 2000; 86(5): 541 - 548. [Abstract] [Full Text] [PDF]

				S. Ghosh, N. B Standen, and M. Galinanes Evidence for mitochondrial KATP channels as effectors of human myocardial preconditioning Cardiovasc Res, March 1, 2000; 45(4): 934 - 940. [Abstract] [Full Text] [PDF]

				T. Sato, N. Sasaki, B. O'Rourke, and E. Marban Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels J. Am. Coll. Cardiol., February 1, 2000; 35(2): 514 - 518. [Abstract] [Full Text] [PDF]

				N. Sasaki, T. Sato, A. Ohler, B. O’Rourke, and E. Marban Activation of Mitochondrial ATP-Dependent Potassium Channels by Nitric Oxide Circulation, February 1, 2000; 101(4): 439 - 445. [Abstract] [Full Text] [PDF]

				T. Miura, Y. Liu, H. Kita, T. Ogawa, and K. Shimamoto Roles of mitochondrial ATP-sensitive K channels and PKC in anti-infarct tolerance afforded by adenosine A1 receptor activation J. Am. Coll. Cardiol., January 1, 2000; 35(1): 238 - 245. [Abstract] [Full Text] [PDF]

				R. M. Fryer, J. T. Eells, A. K. Hsu, M. M. Henry, and G. J. Gross Ischemic preconditioning in rats: role of mitochondrial KATP channel in preservation of mitochondrial function Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H305 - H312. [Abstract] [Full Text] [PDF]

				T. Sato Signaling in Late Preconditioning : Involvement of Mitochondrial KATP Channels Circ. Res., December 3, 1999; 85(12): 1113 - 1114. [Full Text] [PDF]

				R. Ockaili, V. R. Emani, S. Okubo, M. Brown, K. Krottapalli, and R. C. Kukreja Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2425 - H2434. [Abstract] [Full Text] [PDF]

				F. Domoki, J. V. Perciaccante, R. Veltkamp, F. Bari, D. W. Busija, and R. M. Bryan Jr Mitochondrial Potassium Channel Opener Diazoxide Preserves Neuronal-Vascular Function After Cerebral Ischemia in Newborn Pigs • Editorial Comment Stroke, December 1, 1999; 30(12): 2713 - 2719. [Abstract] [Full Text] [PDF]

				D. Belhomme, J. Peynet, M. Louzy, J.-M. Launay, M. Kitakaze, and P. Menasche Evidence for Preconditioning by Isoflurane in Coronary Artery Bypass Graft Surgery Circulation, November 9, 1999; 100 (2009): II-340 - II-344. [Abstract] [Full Text] [PDF]