Wh. Dubell et al., Independent inhibition of calcineurin and K+ currents by the immunosuppressant FK-506 in rat ventricle, AM J P-HEAR, 44(6), 1998, pp. H2041-H2052
Citations number
34
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
FK-506 increases the cytosolic Ca2+ concentration transient in rat ventricu
lar myocytes by prolonging the action potential through inhibition of the K
+ currents I-to and I-K [J. Physiol. (Lond.) 501: 509-516, 1997]. Physiolog
ical and biochemical techniques were used in parallel to examine the electr
ophysiological mechanisms and the role of calcineurin inhibition in these e
ffects. FK-506 prolonged the recovery of I-to from inactivation. Thus I-to
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 I-K (similar to 60%) was time and voltage independent. At 25 mu M, FK-50
6 (by 65%) and cyclosporinA(by 57%) inhibited calcineurin activity in myocy
te extracts. However, only FK-506 increased the cytosolic Ca2+ concentratio
n transient in field-stimulated myocytes. Furthermore, FK-506 was still act
ive on K+ currents when cells were dialyzed with 10 mM EGTA. These results
demonstrate that calcineurin inhibition is not responsible for the function
al effects of FK-506 in heart and suggest that I-K and I-to are modulated b
y FK-506-binding proteins or directly by FK-506.