Independent inhibition of calcineurin and K+ currents by the immunosuppressant FK-506 in rat ventricle.
FK-506 increases the cytosolic Ca2+ concentration transient in rat ventricular myocytes by prolonging the action potential through inhibition of the K+ currents Ito and IK [J. Physiol. (Lond.) 501: 509-516, 1997]. Physiological and biochemical techniques were used in parallel to examine the electrophysiological mechanisms and the role of calcineurin inhibition in these effects. FK-506 prolonged the recovery of Ito from inactivation. Thus Ito inhibition was frequency dependent, with no decrease at 0.2 Hz (recorded at +50 mV from -70 mV) but a 40% decrease at 2.0 Hz. In contrast, inhibition of IK ( approximately 60%) was time and voltage independent. At 25 microM, FK-506 (by 65%) and cyclosporin A (by 57%) inhibited calcineurin activity in myocyte extracts. However, only FK-506 increased the cytosolic Ca2+ concentration transient in field-stimulated myocytes. Furthermore, FK-506 was still active on K+ currents when cells were dialyzed with 10 mM EGTA. These results demonstrate that calcineurin inhibition is not responsible for the functional effects of FK-506 in heart and suggest that IK and Ito are modulated by FK-506-binding proteins or directly by FK-506.
duBell
W H
WH
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, USA.
Gaa
S T
ST
Lederer
W J
WJ
Rogers
T B
TB
D000818:Animals; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D002469:Cell Separation; D016572:Cyclosporine / Q000494:pharmacology; D004553:Electric Conductivity; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles; D006706:Homeostasis; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009994:Osmolar Concentration; D011188:Potassium / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000494:pharmacology*
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; D011188:Potassium; D002118:Calcium; D016559:Tacrolimus