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(Circulation Research. 2008;103:1458.)
© 2008 American Heart Association, Inc.

Cellular Biology

Differential Structure of Atrial and Ventricular K_ATP

Atrial K_ATP Channels Require SUR1

Thomas P. Flagg, Harley T. Kurata, Ricard Masia, George Caputa, Mark A. Magnuson, David J. Lefer, William A. Coetzee, Colin G. Nichols

From the Department of Cell Biology and Physiology (T.P.F., H.T.K., R.M., G.C., C.G.N.), Washington University School of Medicine, St Louis, Mo; Department of Molecular Physiology and Biophysics (M.A.M.), Vanderbilt University School of Medicine, Nashville, Tenn; Department of Medicine and Pathology (D.J.L.), Albert Einstein College of Medicine, New York; and Department of Pediatrics (W.A.C.), New York University School of Medicine.

Correspondence to Colin G. Nichols, PhD, Department of Cell Biology and Physiology, Box 8228, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. E-mail cnichols{at}wustl.edu

The isoform-specific structure of the ATP-sensitive potassium (K_ATP) channel endows it with differential fundamental properties, including physiological activation and pharmacology. Numerous studies have convincingly demonstrated that the pore-forming Kir6.2 (KCNJ11) and regulatory SUR2A (ABCC9) subunits are essential elements of the sarcolemmal K_ATP channel in cardiac ventricular myocytes. Using a novel antibody directed against the COOH terminus of SUR1 (ABCC8), we show that this K_ATP subunit is also expressed in mouse myocardium and is the dominant SUR isoform in the atrium. This suggests differential sarcolemmal K_ATP composition in atria and ventricles, and, to test this, K_ATP currents were measured in isolated atrial and ventricular myocytes from wild-type and SUR1^–/– animals. K_ATP conductance is essentially abolished in SUR1^–/– atrial myocytes but is normal in SUR1^–/– ventricular myocytes. Furthermore, pharmacological properties of wild-type atrial K_ATP match closely the properties of heterologously expressed SUR1/Kir6.2 channels, whereas ventricular K_ATP properties match those of heterologously expressed SUR2A/Kir6.2 channels. Collectively, the data demonstrate a previously unappreciated K_ATP channel heterogeneity: SUR1 is an essential component of atrial, but not ventricular, K_ATP channels. Differential molecular make-up of the 2 channels underlies differential pharmacology, with important implications when considering sulfonylurea therapy or dissecting the role of cardiac K_ATP pharmacologically, as well as for understanding of the role of diazoxide in preconditioning.

Key Words: diazoxide • sarcolemmal • mitochondrial • ABCC8 • ABCC9

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