Mechanisms of Disease: ryanodine receptor defects in heart failure and fatal arrhythmia.
Abnormal regulation of intracellular Ca(2+) by sarcoplasmic reticulum plays a part in the mechanism underlying contractile and relaxation dysfunction in heart failure (HF). The protein-kinase-A-mediated hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum has been shown to cause the dissociation of FKBP12.6 (also known as calstabin-2) from ryanodine receptors in HF. In addition, several disease-linked mutations in the ryanodine receptors have been reported in patients with catecholaminergic polymorphic ventricular tachycardia or arrhythmogenic right ventricular cardiomyopathy type 2. The unique distribution of these mutation sites has led to the concept that the interaction among the putative regulatory domains within the ryanodine receptors has a key role in regulating channel opening. The knowledge gained from various studies of ryanodine receptors under pathologic conditions might lead to the development of new pharmacological or genetic strategies for the treatment of HF or cardiac arrhythmia. In this review, we focus on the role of the Ca(2+)-release channel, the ryanodine receptor, in the pathogenesis of HF and fatal arrhythmia, and the possibility of developing new therapeutic strategies for targeting this receptor.
Yano
Masafumi
M
Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Yamamoto
Takeshi
T
Ikeda
Yasuhiro
Y
Matsuzaki
Masunori
M
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D015996:Survival Rate
D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D019837:Ryanodine Receptor Calcium Release Channel