Luo W, Grupp I L, Harrer J, Ponniah S, Grupp G, Duffy J J, Doetschman T, Kranias E G
Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, OH 45267-0575.
Circ Res. 1994 Sep;75(3):401-9. doi: 10.1161/01.res.75.3.401.
Phospholamban is the regulator of the Ca(2+)-ATPase in cardiac sarcoplasmic reticulum (SR), and it has been suggested to be an important determinant in the inotropic responses of the heart to beta-adrenergic stimulation. To determine the role of phospholamban in vivo, the gene coding for this protein was targeted in murine embryonic stem cells, and mice deficient in phospholamban were generated. The phospholamban-deficient mice showed no gross developmental abnormalities but exhibited enhanced myocardial performance without changes in heart rate. The time to peak pressure and the time to half-relaxation were significantly shorter in phospholamban-deficient mice compared with their wild-type homozygous littermates as assessed in work-performing mouse heart preparations under identical venous returns, afterloads, and heart rates. The first derivatives of intraventricular pressure (+/- dP/dt) were also significantly elevated, and this was associated with an increase in the affinity of the SR Ca(2+)-ATPase for Ca2+ in the phospholamban-deficient hearts. Baseline levels of these parameters in the phospholamban-deficient hearts were equal to those observed in hearts of wild-type littermates maximally stimulated with the beta-agonist isoproterenol. These findings indicate that phospholamban acts as a critical repressor of basal myocardial contractility and may be the key phosphoprotein in mediating the heart's contractile responses to beta-adrenergic agonists.
受磷蛋白是心肌肌浆网（SR）中Ca(2+)-ATP酶的调节因子，有人认为它是心脏对β-肾上腺素能刺激产生变力反应的一个重要决定因素。为了确定受磷蛋白在体内的作用，编码该蛋白的基因在小鼠胚胎干细胞中被靶向，从而培育出缺乏受磷蛋白的小鼠。缺乏受磷蛋白的小鼠没有明显的发育异常，但心肌功能增强，心率没有变化。在相同静脉回流、后负荷和心率条件下，对工作状态的小鼠心脏标本进行评估，结果显示，与野生型纯合子同窝小鼠相比，缺乏受磷蛋白的小鼠达到峰值压力的时间和半舒张时间明显缩短。室内压的一阶导数（+/- dP/dt）也显著升高，这与缺乏受磷蛋白的心脏中肌浆网Ca(2+)-ATP酶对Ca2+的亲和力增加有关。缺乏受磷蛋白的心脏中这些参数的基线水平与用β-激动剂异丙肾上腺素最大程度刺激的野生型同窝小鼠心脏中观察到的水平相当。这些发现表明，受磷蛋白是基础心肌收缩力的关键抑制因子，可能是介导心脏对β-肾上腺素能激动剂收缩反应的关键磷蛋白。
