Molecular basis of cardiac potassium channel stimulation by protein kinase A

Cardiac beta-adrenergic receptors accelerate heart rate by modulating ionic currents through a pathway involving cyclic AMP-dependent protein kinase A (PKA). Previous studies have focused on the regulation of Ca2+ channels by PKA; however, due to the heterogeneity of K+ channels expressed within the heart, little is known about the mechanism by which PKA modulates individual K+ channels. Here we report that PKA strongly enhanced the activity of a cloned delayed rectifier K+ channel that is normally expressed in cardiac atria. This effect required a single PKA consensus phosphorylation site located near the amino terminus of the channel protein. Furthermore, patch clamp analysis revealed that PKA phosphorylation increased the open time that single channels spend in higher conductance states. These studies provide evidence that hormonal modulation of a cardiac K+ channel involves direct phosphorylation by PKA.