Distinct voltage-dependent regulation of a heart-delayed IK by protein kinases A and C

We have investigated the effects of stimulation of adenosine 3',5'-cyclic monophosphate-dependent protein kinase (protein kinase A) and Ca(2+)-diacylglycerol-dependent protein kinase (protein kinase C) on the delayed rectifier K+ current (IK) in guinea pig ventricular cells using a whole cell arrangement of the patch-clamp procedure. Stimulation of either protein kinase C or A resulted in enhanced IK activity. Augmentation of IK observed during stimulation of protein kinase A occurred in a markedly voltage-dependent manner, with the largest increases occurring at potentials near the threshold for IK activation. Enhancement of IK during stimulation of protein kinase C followed a different pattern, with minimal effects of the enzyme near IK threshold. Neither protein kinase A nor C altered the kinetics of IK activation, although both kinases slightly changed the kinetics of deactivation. Both kinases increased IK maximal conductance, but the effects of each kinase on the voltage-dependence of activation differed. Protein kinase A shifted IK activation toward more negative voltages but did not affect the slope of the activation curve. Protein kinase C, in contrast, changed the slope of the IK activation curve, with only a small effect on the half-maximal voltage of activation. These contrasting effects on the voltage dependence of IK activation are consistent with actions of the kinases at distinct sites on or near the IK channel protein.