Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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Calcineurin
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Calcium Channels / isolation & purification
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Calcium Channels / metabolism*
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Calmodulin-Binding Proteins / antagonists & inhibitors
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Calmodulin-Binding Proteins / metabolism
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Carrier Proteins / biosynthesis
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Carrier Proteins / isolation & purification
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Carrier Proteins / metabolism*
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Cell Line
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DNA Primers
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / isolation & purification
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DNA-Binding Proteins / metabolism*
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Dogs
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Gene Expression
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Heat-Shock Proteins / biosynthesis
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Heat-Shock Proteins / isolation & purification
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Heat-Shock Proteins / metabolism*
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Humans
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Mammals
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Molecular Sequence Data
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Muscle Proteins / isolation & purification
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Muscle Proteins / metabolism*
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Myocardium / metabolism*
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / metabolism
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Polyenes / metabolism
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Polymerase Chain Reaction
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Rabbits
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / metabolism
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Ryanodine / metabolism
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Ryanodine Receptor Calcium Release Channel
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Sirolimus
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Species Specificity
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Tacrolimus / metabolism*
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Tacrolimus / pharmacology
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Tacrolimus Binding Proteins
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Transfection
Substances
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Calcium Channels
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Calmodulin-Binding Proteins
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Carrier Proteins
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DNA Primers
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DNA-Binding Proteins
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Heat-Shock Proteins
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Muscle Proteins
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Polyenes
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Recombinant Proteins
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Ryanodine Receptor Calcium Release Channel
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Ryanodine
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Calcineurin
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Phosphoprotein Phosphatases
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Tacrolimus Binding Proteins
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Sirolimus
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Tacrolimus