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(Circulation. 2005;111:3400-3410.)
© 2005 American Heart Association, Inc.

Heart Failure

Defective Regulation of Interdomain Interactions Within the Ryanodine Receptor Plays a Key Role in the Pathogenesis of Heart Failure

Tetsuro Oda, MD^*; Masafumi Yano, MD, PhD^*; Takeshi Yamamoto, MD, PhD; Takahiro Tokuhisa, MD; Shinichi Okuda, MD, PhD; Masahiro Doi, MD, PhD; Tomoko Ohkusa, MD, PhD; Yasuhiro Ikeda, MD, PhD; Shigeki Kobayashi, MD, PhD; Noriaki Ikemoto, PhD; Masunori Matsuzaki, MD, PhD

From the Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan (T.O., M.Y., T.Y., T.T., S.O., M.D., T.O., Y.I., S.K., M.M.), and Boston Biomedical Research Institute, Watertown, and Department of Neurology, Harvard Medical School, Boston (N.I.), Mass.

Correspondence to Masafumi Yano, MD, PhD, Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan. E-mail yanoma{at}yamaguchi-u.ac.jp

Received September 22, 2004; revision received February 19, 2005; accepted March 2, 2005.

Background— According to our hypothesis, 2 domains within the ryanodine receptor (RyR) of sarcoplasmic reticulum (SR) (N-terminal [0 to 600] and central [2000 to 2500] domains), where many mutations have been found in patients with polymorphic ventricular tachycardia, interact with each other as a regulatory switch for channel gating. Here, we investigated whether the defective FKBP12.6-mediated stabilization of RyR in heart failure is produced by an abnormal interdomain interaction.

Methods and Results— SR vesicles were isolated from dog left ventricular muscles, and then the RyR moiety of the SR was fluorescently labeled with methylcoumarin acetate (MCA) using DPc10, a synthetic peptide corresponding to Gly²⁴⁶⁰-Pro²⁴⁹⁵ of RyR (one of the mutable domains in polymorphic ventricular tachycardia), as a site-directing carrier; the carrier was removed from the RyR after MCA labeling. Addition of DPc10 induced an unzipped state of the interacting N-terminal and central domains, as evidenced by an increase in the accessibility of the RyR-bound MCA fluorescence to a large fluorescence quencher. Domain unzipping resulted in Ca²⁺ leak through the RyR and facilitated cAMP-dependent hyperphosphorylation of RyR and FKBP12.6 dissociation from RyR. When DPc10 was introduced into the isolated myocytes, the magnitude of intracellular Ca²⁺ transient decreased, and its decay time was prolonged. In the SR isolated from pacing-induced dog failing hearts, the domain unzipping has already occurred, together with FKBP12.6 dissociation and Ca²⁺ leak.

Conclusions— The specific domain interaction within the RyR regulates the channel gating property, and the defectiveness in the mode of the interdomain interaction seems to be the initial critical step of the pathogenesis of heart failure.

Key Words: calcium • heart failure • ion channels • sarcoplasmic reticulum

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Stephan E. Lehnart, Xander H.T. Wehrens, and Andrew R. Marks
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