Differential Structure of Atrial and Ventricular KATP Atrial KATP Channels Require SUR1

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. (Circ Res. 2008;103:1458-1465.)