Abstract
FK506 binding proteins (FKBPs 12 and 12.6) interact with ryanodine receptor (RyR) and modulate its functions. FK506 binds to and reverses effects of FKBP on RyR, thus increasing RyR sensitivity to Ca2+, decreasing RyR cooperativity, and increasing RyR open probability. FK506 would thus be expected to have an effect on excitation-contraction coupling, but which of these FK506 effects predominates and how the [Ca2+]i transient would be altered are difficult to predict. FK506 has been reported to increase the [Ca2+]i transient in rat myocytes, but effects in other species have not been described. We compared the effects of FK506 on [Ca2+]i transients, L-type Ca2+ channel and Na/Ca exchange currents, membrane potential, and sarcoplasmic reticulum (SR) Ca2+ content in adult mouse and rabbit ventricular myocytes (VM). FK506 (10 microM) increased the [Ca2+]i transient in mouse VM (656 +/- 116 to 945 +/- 144 nM, p < 0.001) but decreased the amplitude of [Ca2+]i transients in rabbit VM (627 +/- 61 to 401 +/- 37 nM, p < 0.001). Similar effects were observed with rapamycin. The effects of FK506 and rapamycin on [Ca2+]i transients in VM of both species were reversible upon washout. FK506 did not alter SR Ca2+ content in mouse VM (0.79 +/- 0.1 versus 0.78 +/- 0.1 pC/pF) but reduced the SR Ca2+ content in rabbit VM (0.43 +/- 0.05 versus 0.30 +/- 0.04 pC/pF, P < 0.05) [pC = the integral (pA. s) of the caffeine-induced inward I(Na/Ca) normalized by cell capacitance (pF)]. FK506 had no effects on membrane potential, I(Ca,L) and outward I(Na/Ca) in either mouse or rabbit VM. These results indicate that alteration of the functions of RyR by FK506-mediated dissociation of FKBP from RyR has different species-dependent effects on SR Ca2+ load and thus [Ca2+]i transients. This difference may result from the fact that [Na+]i is low in rabbit myocytes, allowing extrusion by Na+/Ca2+ exchange of Ca2+ released by FK506-induced dissociation of FKBP12.6 from SR RyR.
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