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(Circulation. 2003;107:378.)
© 2003 American Heart Association, Inc.

Editorial

Treatment of Heart Failure Through Stabilization of the Cardiac Ryanodine Receptor

Gerd Hasenfuss, MD; Tim Seidler, MD

From the Department of Cardiology and Pneumology, University of Göttingen, Göttingen, Germany.

Correspondence to Gerd Hasenfuss, MD, University of Göttingen, Cardiology and Pneumology, Robert-Koch-Straße 40, 37075 Göttingen, Germany. E-mail hasenfus@med.uni-goettingen.de

Key Words: Editorials • heart failure • calcium • sarcoplasmic reticulum

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The key event in cardiac excitation-contraction coupling is calcium-induced calcium release from the sarcoplasmic reticulum (SR) after activation of cardiac ryanodine receptors (RyRs).¹ Two distinct genes encode the cardiac (RyR2) and skeletal muscle (RyR1) specific receptors.^2,3 A third type of ryanodine receptor (RyR3) exhibits functional properties distinct from those of RyR1 and RyR2.⁴ The RyR channels form a tetrameric structure composed of 4 monomeric subunits, each of about 565 000 Daltons. These channels are about 10 times larger than the voltage-gated Ca²⁺ and Na⁺ channels.⁵ RyR2 opening increases cytosolic Ca²⁺ from approximately 100 nmol/L to 1 µmol/L with consecutive activation of contractile proteins. The RyR was recently shown to be a macromolecular complex including protein kinase A (PKA) and its anchoring protein (mAKAP), the protein phosphatases PP1 and PP2A, sorcin, calmodulin, FK506 binding protein (FKBP), and other proteins.⁵ FKBP12.0 and its isoform FKBP12.6 seem to play an important role for the regulation of the RyR. The immunophilin FKBP12 was originally identified as the cytosolic receptor for the immunosuppressant FK506 in T-cells. FKBP12 is a cis/trans peptidyl-prolyl isomerase. However, it is unlikely that this enzymatic activity is directly involved in RyR regulation. FKBP12 has been postulated to bind to the RyR with a stoichiometry of 4 or less FKBP12 molecules per single functional channel.⁶ FKBP12.0 is tightly bound to and regulates the function of the skeletal RyR1, whereas RyR2 has been found to co-purify selectively with FKBP12.6 despite a higher expression level of FKBP12.0 in cardiac myocytes.⁷ However, considerable species differences . . . [Full Text of this Article]

Related Article:

FKBP12.6-Mediated Stabilization of Calcium-Release Channel (Ryanodine Receptor) as a Novel Therapeutic Strategy Against Heart Failure

Masafumi Yano, Shigeki Kobayashi, Masateru Kohno, Masahiro Doi, Takahiro Tokuhisa, Shinichi Okuda, Masae Suetsugu, Takayuki Hisaoka, Masakazu Obayashi, Tomoko Ohkusa, Michihiro Kohno, and Masunori Matsuzaki
Circulation 2003 107: 477-484. [Abstract] [Full Text]

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