TY - JOUR
T1 - A novel FK506 binding protein can mediate the immunosuppressive effects of FK506 and is associated with the cardiac ryanodine receptor
AU - Lam, Elsa
AU - Martin, Mary M.
AU - Timerman, Anthony P.
AU - Sabers, Candace
AU - Fleischer, Sidney
AU - Lukas, Thomas
AU - Abraham, Robert T.
AU - O'Keefe, Stephen J.
AU - O'Neill, Edward A.
AU - Wiederrecht, Gregory J.
PY - 1995/11/3
Y1 - 1995/11/3
N2 - FK506, an immunosuppressant that prolongs allograft survival, is a co- drug with its intracellular receptor, FKBP12. The FKBP12·FK506 complex inhibits calcineurin, a critical signaling molecule during T-cell activation. FKBP12 was, until recently, the sole FKBP known to mediate calcineurin inhibition at clinically relevant FK506 concentrations. The best characterized cellular function of FKBP12 is the modulation of ryanodine receptor isoform-1, a component of the calcium release channel of skeletal muscle sarcoplasmic reticulum. Recently, a novel protein, FKBP12.6, was found to inhibit calcineurin at clinically relevant FK506 concentrations. We have cloned the cDNA encoding human FKBP12.6 and characterized the protein. In transfected Jurkat cells, FKBP12.6 is equivalent to FKBP12 at mediating the inhibitory effects of FK506. Upon binding rapamycin, FKBP12.6 complexes with the 288-kDa mammalian target of rapamycin. In contrast to FKBP12, FKBP12.6 is not associated with ryanodine receptor isoform-1 but with the distinct ryanodine receptor isoform-2 in cardiac muscle sarcoplasmic reticulum. Our results suggest that FKBP12.6 has both a unique physiological role in excitation-contraction coupling in cardiac muscle and the potential to contribute to the immunosuppressive and toxic effects of FK506 and rapamycin.
AB - FK506, an immunosuppressant that prolongs allograft survival, is a co- drug with its intracellular receptor, FKBP12. The FKBP12·FK506 complex inhibits calcineurin, a critical signaling molecule during T-cell activation. FKBP12 was, until recently, the sole FKBP known to mediate calcineurin inhibition at clinically relevant FK506 concentrations. The best characterized cellular function of FKBP12 is the modulation of ryanodine receptor isoform-1, a component of the calcium release channel of skeletal muscle sarcoplasmic reticulum. Recently, a novel protein, FKBP12.6, was found to inhibit calcineurin at clinically relevant FK506 concentrations. We have cloned the cDNA encoding human FKBP12.6 and characterized the protein. In transfected Jurkat cells, FKBP12.6 is equivalent to FKBP12 at mediating the inhibitory effects of FK506. Upon binding rapamycin, FKBP12.6 complexes with the 288-kDa mammalian target of rapamycin. In contrast to FKBP12, FKBP12.6 is not associated with ryanodine receptor isoform-1 but with the distinct ryanodine receptor isoform-2 in cardiac muscle sarcoplasmic reticulum. Our results suggest that FKBP12.6 has both a unique physiological role in excitation-contraction coupling in cardiac muscle and the potential to contribute to the immunosuppressive and toxic effects of FK506 and rapamycin.
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U2 - 10.1074/jbc.270.44.26511
DO - 10.1074/jbc.270.44.26511
M3 - Article
C2 - 7592869
AN - SCOPUS:0028785482
SN - 0021-9258
VL - 270
SP - 26511
EP - 26522
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 44
ER -