Abstract
An abnormal regulation of intracellular Ca2+ by sarcoplasmic reticulum (SR) has been shown to be involved in the mechanism underlying contractile and relaxation dysfunction in heart failure. PKA-mediated hyperphosphorylation of ryanodine receptors (RyR) in SR was found to cause dissociation of FKBP12.6 from RyR in heart failure. This results in an abnormal Ca2+ leak through RyR, leading to increased cytosolic diastolic Ca2+ concentration, prolongation in the Ca2+ transient, and delayed/slowed diastolic decline in cytosolic Ca2+ concentration. We previously demonstrated that both beta-blocker and a cardioprotective drug JTV519 restores the defective FKBP12.6-mediated regulation of RyR channel gating, having an improvement of cardiac contractile and relaxation functions during the development of pacing-induced heart failure. Here, using domain-probe technique we further assessed the fundamental mechanism of abnormal Ca2+ regulatory process within RyR in heart failure. A synthetic peptide corresponding to the Gly2460-Pro2495 domain of the RyR2, designated DPc10, induced 1) unzipping mode of N-terminal and central domain interaction, 2) Ca2+ leak by itself, 3) facilitated FKBP12.6 dissociation, 4) prolongation of Ca2+ transient in myocyte. Thus, defective domain interaction within RyR (N-terminal and central) critically regulates the gating property of RyR2 in the pathogenic mechanism of heart failure, and therefore it may be a new therapeutic target against heart failure. [Jpn J Physiol 55 Suppl:S55 (2005)]
