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.