Koss K L, Grupp I L, Kranias E G
Dept. of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio 45267-0575, USA.
Basic Res Cardiol. 1997;92 Suppl 1:17-24. doi: 10.1007/BF00794064.
Phospholamban is a regulatory phosphoprotein which modulates the active transport of Ca2+ by the cardiac sarcoplasmic reticular Ca(2+)-ATPase enzyme (SERCA2) into the lumen of the sarcoplasmic reticulum. Phospholamban, which is a reversible inhibitor of SERCA2, represses the enzyme's activity, and this inhibition is relieved upon phosphorylation of phospholamban in response to beta-adrenergic stimulation. In this way, phospholamban is an important regulator of SERCA2-mediated myocardial relaxation during diastole. This report centers on the hypothesis that the relative levels of phospholamban: SERCA2 in cardiac muscle plays an important role in the muscle's overall contractility status. This hypothesis was tested by comparing the contractile parameters of: a) murine atrial and ventricular muscles, which differentially express phospholamban, and b) murine wild-type and phospholamban knock-out hearts. These comparisons revealed that atrial muscles, which have a 4.2-fold lower phospholamban: SERCA2 ratio than ventricular muscles, exhibited rates of force development and relaxation of tension, which were three-fold faster that these parameters for ventricular muscles. Similar comparisons were made via analyses of left-ventricular pressure development recorded for isolated, work-performing hearts from wild-type and phospholamban knock-out mice. In these studies, hearts from phospholamban knock-out mice, which were devoid of phospholamban, exhibited enhanced parameters of left-ventricular contractility in comparison to wild-type hearts. These results suggest that the relative phospholamban: SERCA2 ratio is critical in the regulation of myocardial contractility and alterations in this ratio may contribute to the functional deterioration observed during heart failure.
受磷蛋白是一种调节性磷蛋白，它可调节心肌肌浆网Ca(2+)-ATP酶（SERCA2）将Ca2+主动转运至肌浆网腔的过程。受磷蛋白是SERCA2的可逆抑制剂，可抑制该酶的活性，而在β-肾上腺素能刺激下，受磷蛋白发生磷酸化后，这种抑制作用会解除。通过这种方式，受磷蛋白是舒张期SERCA2介导的心肌舒张的重要调节因子。本报告聚焦于这样一个假说：心肌中受磷蛋白与SERCA2的相对水平在肌肉的整体收缩状态中起重要作用。通过比较以下各项的收缩参数来验证这一假说：a）差异表达受磷蛋白的小鼠心房肌和心室肌，以及b）小鼠野生型心脏和受磷蛋白基因敲除心脏。这些比较显示，心房肌的受磷蛋白与SERCA2比值比心室肌低4.2倍，其力量发展速率和张力松弛速率比心室肌的这些参数快三倍。通过分析野生型和受磷蛋白基因敲除小鼠分离的、进行工作的心脏所记录的左心室压力发展情况，进行了类似的比较。在这些研究中，与野生型心脏相比，缺乏受磷蛋白的受磷蛋白基因敲除小鼠的心脏表现出增强的左心室收缩参数。这些结果表明，受磷蛋白与SERCA2的相对比值在心肌收缩调节中至关重要，该比值的改变可能导致心力衰竭期间观察到的功能恶化。
