Abnormal ryanodine receptor function in heart failure.
The abnormally regulated release of Ca2+ from an intracellular Ca2+ store, the sarcoplasmic reticulum (SR), is the mechanism underlying contractile and relaxation dysfunctions in heart failure (HF). According to recent reports, protein kinase A (PKA)-mediated hyperphosphorylation of ryanodine receptor (RyR) in the SR has been shown to cause the dissociation of FK506 binding protein (FKBP) 12.6 from the RyR in heart failure. This causes an abnormal Ca2+ leak through the Ca2+ channel located in the RyR, leading to an increase in the cytosolic Ca2+ during diastole, prolongation of the Ca2+ transient, and delayed/slowed diastolic Ca2+ re-uptake. More recently, a considerable number of disease-linked mutations in the RyR have been reported in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) or arrhythmogenic right ventricular dysplasia type 2. An analysis of the disposition of these mutation sites within well-defined domains of the RyR polypeptide chain has led to the new concept that interdomain interactions among these domains play a critical role in channel regulation, and an altered domain interaction causes channel dysfunction in the failing heart. The knowledge gained from the recent literature concerning the critical proteins and the changes in their properties under pathological conditions has brought us to a better position to develop new pharmacological or genetic strategies for the treatment of heart failure or cardiac arrhythmia. A considerable body of evidence reviewed here indicates that abnormal RyR function plays an important role in the pathogenesis of heart failure. This review also covers some controversial issues in the literature concerning the involvement of phosphorylation and FKBP12.6.
Yano
Masafumi
M
Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan. yanoma@po.cc.yamaguchi-u.ac.jp
Yamamoto
Takeshi
T
Ikemoto
Noriaki
N
Matsuzaki
Masunori
M
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D015640:Ion Channel Gating; D046911:Macromolecular Substances; D009200:Myocardial Contraction / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D017180:Tachycardia, Ventricular
D015220:Calcium Channels; D046911:Macromolecular Substances; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium