Kontula Kimmo, Laitinen Päivi J, Lehtonen Annukka, Toivonen Lauri, Viitasalo Matti, Swan Heikki
Department of Medicine, University of Helsinki, 00290 Helsinki, Finland.
Cardiovasc Res. 2005 Aug 15;67(3):379-87. doi: 10.1016/j.cardiores.2005.04.027.
Cardiac excitation-contraction coupling occurs by a calcium ion-mediated mechanism in which the signal of action potential is converted into Ca2+ influx into the cardiomyocytes through the sarcolemmal L-type calcium channels. This is followed by Ca2+-induced release of additional Ca2+ ions from the lumen of the sarcoplasmic reticulum into the cytosol via type 2 ryanodine receptors (RyR2). RyR2 channels form large complexes with additional regulatory proteins, including FKBP12.6 and calsequestrin 2 (CASQ2). Catecholamines, released into the body fluids during emotional or physical stress, activate Ca2+-induced Ca2+ release by protein kinase A-mediated phosphorylation of RyR2. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an insidious, early-onset and highly malignant, inherited disorder characterized by effort-induced ventricular arrhythmias in the absence of structural alterations of the heart. At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT. Mutations of the RyR2 gene cause autosomal dominant CPVT, while mutations of the CASQ2 gene may cause an autosomal recessive or dominant form of CPVT. The steps of the molecular pathogenesis of CPVT are not entirely clear, but inappropriate "leakiness" of RyR2 channels is thought to play a role; the underlying mechanisms may involve an increase in the basal activity of the RyR2 channel, alterations in its phosphorylation status, a defective interaction of RyR2 with other molecules or ions, such as FKBP12.6, CASQ2, or Mg2+, or its abnormal activation by extra- or intraluminal Ca2+ ions. Beta-adrenergic antagonists have proven to be of value in prevention of arrhythmias in CPVT patients, but occasional treatment failures call for alternative measures. There is great interest at present for the development of novel antiarrhythmic drugs for CPVT, as the same approaches may be applied for treatment of more common forms of life-threatening arrhythmias, such as those arising during ischemia and heart failure.
心脏兴奋-收缩偶联通过钙离子介导的机制发生，在该机制中，动作电位信号通过肌膜L型钙通道转化为Ca2+流入心肌细胞。随后，Ca2+诱导额外的Ca2+离子从肌浆网腔通过2型兰尼碱受体（RyR2）释放到胞质溶胶中。RyR2通道与包括FKBP12.6和肌集钙蛋白2（CASQ2）在内的其他调节蛋白形成大的复合物。在情绪或身体应激期间释放到体液中的儿茶酚胺通过蛋白激酶A介导的RyR2磷酸化激活Ca2+诱导的Ca2+释放。儿茶酚胺能多形性室性心动过速（CPVT）是一种隐匿性、早发性且高度恶性的遗传性疾病，其特征是在心脏无结构改变的情况下运动诱发室性心律失常。至少一些年轻人突然不明原因死亡的病例可能归因于CPVT。RyR2基因突变导致常染色体显性CPVT，而CASQ2基因突变可能导致常染色体隐性或显性形式的CPVT。CPVT分子发病机制的步骤尚不完全清楚，但RyR2通道不适当的“渗漏”被认为起作用；潜在机制可能包括RyR2通道基础活性增加、其磷酸化状态改变、RyR2与其他分子或离子（如FKBP12.6、CASQ2或Mg2+）的相互作用缺陷，或其被胞外或胞内Ca2+离子异常激活。β-肾上腺素能拮抗剂已被证明对预防CPVT患者的心律失常有价值，但偶尔的治疗失败需要采取替代措施。目前对开发用于CPVT的新型抗心律失常药物非常感兴趣，因为相同的方法可能适用于治疗更常见的危及生命的心律失常形式，如缺血和心力衰竭期间出现的心律失常。
