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1 Department of Biochemistry and Molecular Biology and 2 Departments of Molecular Biology and Biophysics and Physiology, Medical Biotechnology Center and School of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201
Modulation of mouse ventricular action potentials and
K+ currents was examined using the whole cell patch-clamp
technique. The composite mouse ventricular K+ current
(consisted of an outward transient followed by a slowly decaying
sustained component. Use of the K+ channel blockers
tetraethylammonium and 4-aminopyridine and a transgenic mouse model
revealed three pharmacologically and kinetically distinct currents:
Ito, which contributed to the transient component; IK, which contributed to the sustained component;
and a slowly activating current (Islow), which
contributed to both components. The immunosuppressant FK-506 increased
action potential duration at 90% repolarization by 66.7% by
decreasing the sustained component (
48% at +60 mV) and
prolonging recovery from inactivation (by 26% at 200 ms) of the
transient component. These effects were isolated to
IK and Ito, respectively.
Rapamycin had strikingly similar effects on these currents. Both FK-506
and rapamycin are known to target the immunophilin FKBP12. Thus we
conclude that FKBP12 modulates specific mouse K+ channels,
and thus the mouse ventricular action potential, by interacting
directly with K+ channel proteins or with other associated
regulatory proteins.
transient outward current; FK-binding proteins; Kv1.5
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