Ryanodine receptor as a new therapeutic target of heart failure and lethal arrhythmia.
Abnormal intracellular Ca(2+) handling by the sarcoplasmic reticulum (SR) is a critical factor in the development of heart failure (HF). Not only decreased Ca(2+) uptake, but also uncoordinated Ca(2+) release plays a significant role in contractile and relaxation dysfunction. Spontaneous Ca(2+) release through ryanodine receptor (RyR) 2, a huge tetrameric protein, during diastole leads to a decrease in the SR Ca(2+) content, and also triggers delayed after depolarization that is a substrate for lethal arrhythmia. Several disease-linked mutations of RyR have been reported in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) or arrhythmogenic right ventricular cardiomyopathy type 2 (ARVC2). The unique distribution of these mutation sites has lead to the concept that an interaction among the putative regulatory domains within RyR may play a key role in regulating channel opening, and that there seems to be a common abnormality in the channel disorder of HF and CPVT/ARVC2. Recent knowledge gained from pathological conditions may lead to the development of a new therapeutic strategy for the treatment of HF or cardiac arrhythmia.
Yano
Masafumi
M
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube 755-8505, Japan. yanoma@yamaguchi-u.ac.jp
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D006801:Humans; D015640:Ion Channel Gating; D008955:Models, Cardiovascular; D008958:Models, Molecular; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2