Pharmacology of the cardiac sarcoplasmic reticulum calcium ATPase-phospholamban interaction
Pharmacology of the cardiac sarcoplasmic reticulum calcium ATPase-phospholamban interaction
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DOI：
10.1111/j.1749-6632.1998.tb08305.x
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发表时间：
1998-01-01
期刊：
影响因子：
--
通讯作者：
Johnson, RG
中科院分区：
文献类型：
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作者：
Johnson, RG
越来越多的证据指出受磷蛋白（PLB）调节心脏肌浆网（SR）钙ATP酶在正常和病理条件下影响心肌细胞内钙处理的动力学中的关键作用。基于数据，已经假设PLB抑制剂（例如，钙ATP酶刺激剂）在心力衰竭的治疗中作为正性兴奋药和正性肌力药具有潜在的重要性。在各种SR钙负荷条件下测量来自基因工程小鼠的皂苷透化心肌中的张力瞬变的实验提供了可以通过操纵钙泵的PLB抑制程度来实现的功能改变的证据。上述假设的检验最终需要心脏钙泵的选择性、高亲和力、膜渗透性小分子刺激剂。心脏钙泵激活剂的筛选产生了一系列发挥明显不同作用机制的药物;有些可能是帮助阐明PLB-钙ATP酶相互作用性质的工具。将探讨PLB作为药物靶点的基本原理、PLB抑制剂的最佳特性以及几种低分子量化合物的特性。
Accumulating evidence points to the critical role of phospholamban (PLB) regulation of the cardiac sarcoplasmic reticulum (SR) calcium ATPase in influencing the kinetics of calcium handling within the cardiac myocyte under normal and pathological conditions, Based on the data, it has been hypothesized that PLB inhibitors (e.g., calcium ATPase stimulators) would be of potential importance as positive lusitropes and inotropes in the treatment of heart failure. Experiments measuring tension transients in saponin-permeabilized cardiac muscles from genetically engineered mice under a variety of SR calcium loading conditions provide evidence of the functional alterations that can be achieved by manipulation of the degree of PLB inhibition of the calcium pump. Testing of the above hypothesis will ultimately require a selective, high-affinity, membrane-permeable small molecule stimulator of the cardiac calcium pump. Screening for cardiac calcium pump activators has produced a series of agents exerting apparently different mechanisms of action; some may be tools to help to elucidate the nature of the PLB-calcium ATPase interaction(s). The rationale for PLB as a drug target, the optimal profile of a PLB inhibitor, and the properties of several low-molecular-weight compounds will be explored.