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Letters to Nature

Nature 416, 334-338 (21 March 2002) | doi:10.1038/416334a; Received 17 September 2001; Accepted 17 December 2001

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Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy

Hong-Bo Xin1,3, Takaaki Senbonmatsu2, Dong-Sheng Cheng1, Yong-Xiao Wang3, Julio A. Copello1, Guang-Ju Ji3, Mei Lin Collier4, Ke-Yu Deng3, Loice H. Jeyakumar1, Mark A. Magnuson5, Tadashi Inagami2, Michael I. Kotlikoff3 & Sidney Fleischer1,6

  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 Fleischer1,6 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).

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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 muscle6, 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 Fleischer1,6 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).