K2p3.1 Protein is Expressed as a Transmural Gradient across the Rat Left Ventricular Free Wall

Introduction: K2p3.1, also known as TASK-1, is a twin-pore acid-sensitive repolarizing K+ channel, responsible for a background potassium current that significantly contributes to setting the resting membrane potential of cardiac myocytes. Inhibition of IK2p3.1 alters cardiac repolarization and is pro-arrhythmogenic. In this study, we have examined the expression of K2p3.1 and function of this channel in tissue and myocytes from across the left ventricular free wall. Methods and Results: Using fluorescence immunocytochemistry, the expression of K2p3.1 protein in myocytes from the sub-endocardial region was found to be twice (205 ± 13.5 %) that found in myocytes from the sub-epicardial region of the left ventricle (100 ± 5.3 %). The left ventricular free-wall exhibited a marked transmural gradient of K2p3.1 protein expression. Western blot analysis confirmed significantly higher K2p3.1 protein expression in sub-endocardial tissue (156 ± 2.5 %) than sub-epicardial tissue (100 ± 5.0 %), however there was no difference in K2p3.1 mRNA expression. Whole cell patch clamp identified IK2p3.1 current density to be significantly greater in myocytes isolated from the sub-endocardium (7.66 ± 0.53 pA/pF) compared with those from the sub-epicardium (3.47 ± 0.74 pA/pF). Conclusions: This is the first study to identify a transmural gradient of K2p3.1 in the left ventricle. This gradient has implications for understanding ventricular arrhythmogenesis under conditions of ischemia but also in response to other modulatory factors such as adrenergic stimulation and the presence of anaesthetics which inhibit or activate this channel.