Beta-adrenergic modulation of cardiac ion channels. Differential temperature sensitivity of potassium and calcium currents.
beta-Adrenergic stimulation of ventricular heart cells results in the enhancement of two important ion currents that regulate the plateau phase of the action potential: the delayed rectifier potassium channel current (IK) and L-type calcium channel current (ICa). The temperature dependence of beta-adrenergic modulation of these two currents was examined in patch-clamped guinea pig ventricular myocytes at various steps in the beta-receptor/cyclic AMP-dependent protein kinase pathway. External applications of isoproterenol and forskolin were used to activate the beta-receptor and the enzyme adenylate cyclase, respectively. Internal dialysis of cyclic 3',5'-adenosine monophosphate (cAMP) or the catalytic subunit of cAMP-dependent protein kinase (CS), as well as the external addition of 8-chlorphenylthio cAMP (CPT-cAMP) was applied to increase intracellular levels of cAMP and CS. Isoproterenol-mediated increases in IK, but not ICa, were found to be very temperature dependent over the range of 20-37 degrees C. At room temperature (20-22 degrees C) isoproterenol produced a large (threefold) enhancement of ICa but had no effect on IK. In contrast, at warmer temperatures (30-37 degrees C) both currents increased in the presence of this agonist and the kinetics of IK were slowed at -30 mV. A similar temperature sensitivity also existed after exposure to forskolin, CPT-cAMP, cAMP, and CS, suggesting that this temperature sensitivity of IK may arise at the channel protein level. Modulation of IK during each of these interventions was accompanied by a slowing in IK kinetics. Thus, regulation of cardiac potassium channels but not calcium channels involves a temperature-dependent step that occurs after activation of the catalytic subunit of cAMP-dependent protein kinase.
Walsh
K B
KB
University of Rochester, School of Medicine and Dentistry, Department of Physiology, New York 14642.
Begenisich
T B
TB
Kass
R S
RS
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002586:Cesium / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004594:Electrophysiology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D011188:Potassium / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013268:Stimulation, Chemical; D013696:Temperature
D007473:Ion Channels; D011943:Receptors, Adrenergic, beta; D002586:Cesium; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D011188:Potassium; D002118:Calcium