Ryanodine receptor as a new therapeutic target of heart failure and lethal arrhythmia.

Abstract

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.

• Authors: Masafumi Yano
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 72 Issue 4 Pg. 509-14 (Apr 2008) ISSN: 1346-9843 [Print] Japan
• PMID: 18362417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Ryanodine Receptor Calcium Release Channel
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Animals
• Arrhythmias, Cardiac (genetics, physiopathology, therapy)
• Calcium Signaling
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (physiology)
• Heart Failure (genetics, physiopathology, therapy)
• Humans
• Ion Channel Gating
• Models, Cardiovascular
• Models, Molecular
• Mutation
• Protein Interaction Domains and Motifs
• Ryanodine Receptor Calcium Release Channel (chemistry, genetics, physiology)