Differential Structure of Atrial and Ventricular K ATP

Abstract

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.