β-Adrenergic regulation of the muscarinic-gated K+ channel via cyclic AMP-dependent protein kinase in atrial cells

Abstract

Cholinergic and β-adrenergic stimulations of ionic currents are major physiological mechanisms in the regulation of heart rate and contractility. Muscarinic receptor stimulation is known to reduce β-adrenergic effects on calcium current via reduction of cyclic AMP. Whether the β-adrenergic stimulation affects the muscarinic response is not known. I report here that the β-adrenergic agonist isoproterenol enhanced the muscarinic-activated K+ channel activity in rat atrial cells. Application of cyclic AMP-dependent protein kinase or its catalytic subunit to the cytoplasmic side of the membrane augmented the acetylcholine-activated K+ channel activity twofold to threefold. Increases in channel activity produced by isoproterenol or cyclic AMP-dependent protein kinase were associated with fourfold to fivefold and approximately twofold increases in the mean open and closed time durations, respectively. Alkaline phosphatase treatment reversesd these effects. These results suggest that cyclic AMP-dependent phosphorylation of the K+ channel or associated regulatory proteins modulates the gating kinetics of the channel. This mechanism may be important in the regulation of pacemaker activity and, thus, the heart rate during β-adrenergic stimulation.