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1 Department of Biochemistry
and Molecular Biology,
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
(~60%) was time and voltage independent. At 25 µM, 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.
immunophilins; transient outward current; potassium current; excitation-contraction coupling
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