K(+) currents responsible for repolarization in mouse ventricle and their modulation by FK-506 and rapamycin.
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: I(to), which contributed to the transient component; I(K), which contributed to the sustained component; and a slowly activating current (I(slow)), 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 I(K) and I(to), 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.
DuBell
W H
WH
Department of Biochemistry and Molecular Biology, Medical Biotechnology Center and School of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Lederer
W J
WJ
Rogers
T B
TB
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004533:Egtazic Acid / Q000494:pharmacology; D004553:Electric Conductivity; D006321:Heart / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D019789:Tetraethylammonium / Q000494:pharmacology; D016276:Ventricular Function
D007166:Immunosuppressive Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D004533:Egtazic Acid; D019789:Tetraethylammonium; D015761:4-Aminopyridine; D002118:Calcium; D020123:Sirolimus; D016559:Tacrolimus