Cardiac defects and altered ryanodine receptor function in mice lacking FKBP 12

Weinian Shou, Bahman Aghdasi, Dawna L. Armstrong, Qiuxia Guo, Shideng Bao, Min Ji Charng, Lawrence M. Mathews, Michael D. Schneider, Susan L. Hamilton, Martin M. Matzuk

Research output: Contribution to journalArticle

335 Scopus citations

Abstract

FKBP12, a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin, is ubiquitously expressed and interacts with proteins in several intracellular signal transduction systems. Although FKBP12 interacts with the cytoplasmic domains of type I receptors of the transforming growth factor-β (TGF-β) superfamily in vitro the function of FKBP12 in TGF-β superfamily signalling is controversial. FKBP12 also physically interacts stoichiometrically with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine receptor (RyR1). In contrast, the cardiac ryanodine receptor, RyR2, appears to bind selectively the FKBP12 homologue, FKBP12.6 (refs 9, 10). To define the functions of FKBP12 in vivo, we generated mutant mice deficient in FKBP12 using embryonic stem (ES) cell technology. FKBP12-deficient mice have normal skeletal muscle but have severe dilated cardiomyopathy and ventricular septal defects that mimic a human congenital heart disorder, noncompaction of left ventricular myocardium. About 9% of the mutants exhibit exencephaly secondary to a defect in neural tube closure. Physiological studies demonstrate that FKBP12 is dispensable for TGF-β-mediated signalling, but modulates the calcium release activity of both skeletal and cardiac ryanodine receptors.

Original languageEnglish (US)
Pages (from-to)489-492
Number of pages4
JournalNature
Volume391
Issue number6666
DOIs
StatePublished - Jan 29 1998
Externally publishedYes

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    Shou, W., Aghdasi, B., Armstrong, D. L., Guo, Q., Bao, S., Charng, M. J., Mathews, L. M., Schneider, M. D., Hamilton, S. L., & Matzuk, M. M. (1998). Cardiac defects and altered ryanodine receptor function in mice lacking FKBP 12. Nature, 391(6666), 489-492. https://doi.org/10.1038/35146