Ather Sameer, Respress Jonathan L, Li Na, Wehrens Xander H T
Dept of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Dept of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, USA.
Biochim Biophys Acta. 2013 Dec;1832(12):2425-31. doi: 10.1016/j.bbadis.2013.06.008. Epub 2013 Jun 14.
Sarcoplasmic reticulum (SR) Ca(2+) release plays an essential role in mediating cardiac myocyte contraction. Depolarization of the plasma membrane results in influx of Ca(2+) through l-type Ca(2+) channels (LTCCs) that in turn triggers efflux of Ca(2+) from the SR through ryanodine receptor type-2 channels (RyR2). This process known as Ca(2+)-induced Ca(2+)release (CICR) occurs within the dyadic region, where the adjacent transverse (T)-tubules and SR membranes allow RyR2 clusters to release SR Ca(2+) following Ca(2+) influx through adjacent LTCCs. SR Ca(2+) released during systole binds to troponin-C and initiates actin-myosin cross-bridging, leading to muscle contraction. During diastole, the cytosolic Ca(2+) concentration is restored by the resequestration of Ca(2+) into the SR by SR/ER Ca(2+)-ATPase (SERCA2a) and by the extrusion of Ca(2+) via the Na(+)/Ca(2+)-exchanger (NCX1). This whole process, entitled excitation-contraction (EC) coupling, is highly coordinated and determines the force of contraction, providing a link between the electrical and mechanical activities of cardiac muscle. In response to heart failure (HF), the heart undergoes maladaptive changes that result in depressed intracellular Ca(2+) cycling and decreased SR Ca(2+) concentrations. As a result, the amplitude of CICR is reduced resulting in less force production during EC coupling. In this review, we discuss the specific proteins that alter the regulation of Ca(2+) during HF. In particular, we will focus on defects in RyR2-mediated SR Ca(2+) release. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.
肌浆网（SR）钙（Ca2+）释放介导心肌细胞收缩，发挥着至关重要的作用。质膜去极化导致Ca2+通过L型钙通道（LTCCs）内流，进而触发Ca2+从SR通过2型兰尼碱受体通道（RyR2）外流。这一过程称为钙诱导钙释放（CICR），发生在二联体区域，相邻的横管（T管）和SR膜使RyR2簇在Ca2+通过相邻LTCCs内流后释放SR Ca2+。收缩期释放的SR Ca2+与肌钙蛋白C结合，启动肌动蛋白-肌球蛋白交叉桥联，导致肌肉收缩。舒张期，通过SR/内质网Ca2+-ATP酶（SERCA2a）将Ca2+重新摄取到SR中以及通过钠/钙交换体（NCX1）排出Ca2+，使胞质Ca2+浓度恢复。这一整个过程，即兴奋-收缩（EC）偶联，高度协调并决定收缩力，在心肌的电活动和机械活动之间建立了联系。心力衰竭（HF）时，心脏会发生适应性不良变化，导致细胞内Ca2+循环减弱和SR Ca2+浓度降低。结果，CICR的幅度减小，导致EC偶联期间产生的力量减少。在本综述中，我们讨论了HF期间改变Ca2+调节的特定蛋白质。特别是，我们将重点关注RyR2介导的SR Ca2+释放缺陷。本文是名为：心力衰竭发病机制及新出现的诊断和治疗干预的特刊的一部分。
