Cardiac defects and altered ryanodine receptor function in mice lacking FKBP12

摘要: FKBP12, a cis–trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin, is ubiquitouslyexpressed interacts with proteins in several intracellular signal transduction systems1.Although FKBP12 cytoplasmic domains of type I receptors transforming growth factor-β(TGF-β) superfamily vitro, function TGF-β signalling iscontroversial2,3,4,5,6. also physicallyinteracts stoichiometrically multiple calcium release channels including tetrameric skeletal muscle ryanodine receptor(RyR1)7,8. In contrast, cardiacryanodine receptor, RyR2, appears to bind selectively theFKBP12 homologue, FKBP12.6 (9, 10). To define functions vivo, we generated mutantmice deficient using embryonic stem (ES) cell technology. FKBP12-deficient mice have normal buthave severe dilated cardiomyopathy ventricular septal defects mimic human congenital heart disorder, noncompaction leftventricular myocardium11,12. About 9% themutants exhibit exencephaly secondary defect neural tube closure. Physiological studies demonstrate dispensable forTGF-β-mediated signalling, but modulates activity both cardiac ryanodinereceptors.