1. Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235, USA
2. Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37235, USA
3. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37235, USA
4. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37235, USA
5. Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA
6. Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Pennsylvania 19104, USA

Correspondence to: Michael I. Kotlikoff³Sidney Fleischer^1,6 Correspondence and requests for materials should be addressed to S.F. (e-mail: Email: sidney.fleischer@vanderbilt.edu) or M.I.K. (e-mail: Email: mik7@cornell.edu).

Abstract

FK506 binding proteins 12 and 12.6 (FKBP12 and FKBP12.6) are intracellular receptors for the immunosuppressant drug FK506 (ref. 1). The skeletal muscle ryanodine receptor (RyR1) is isolated as a hetero-oligomer with FKBP12 (ref. 2), whereas the cardiac ryanodine receptor (RyR2) more selectively associates with FKBP12.6 (refs 3, 4, 5). FKBP12 modulates Ca²⁺ release from the sarcoplasmic reticulum in skeletal muscle^{6, 7} and developmental cardiac defects have been reported in FKBP12-deficient mice⁸, but the role of FKBP12.6 in cardiac excitation–contraction coupling remains unclear. Here we show that disruption of the FKBP12.6 gene in mice results in cardiac hypertrophy in male mice, but not in females. Female hearts are normal, despite the fact that male and female knockout mice display similar dysregulation of Ca²⁺ release, seen as increases in the amplitude and duration of Ca²⁺ sparks and calcium-induced calcium release gain. Female FKBP12.6-null mice treated with tamoxifen, an oestrogen receptor antagonist, develop cardiac hypertrophy similar to that of male mice. We conclude that FKBP12.6 modulates cardiac excitation–contraction coupling and that oestrogen plays a protective role in the hypertrophic response of the heart to Ca²⁺ dysregulation.

1. Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235, USA
2. Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37235, USA
3. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37235, USA
4. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37235, USA
5. Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA
6. Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Pennsylvania 19104, USA

Correspondence to: Michael I. Kotlikoff³Sidney Fleischer^1,6 Correspondence and requests for materials should be addressed to S.F. (e-mail: Email: sidney.fleischer@vanderbilt.edu) or M.I.K. (e-mail: Email: mik7@cornell.edu).