Pharmacology of the cardiac sarcoplasmic reticulum calcium ATPase-phospholamban interaction

被引:12
|
作者
Johnson, RG [1 ]
机构
[1] Merck Res Labs, Dept Pharmacol, W Point, PA 19486 USA
来源
CARDIAC SARCOPLASMIC RETICULUM FUNCTION AND REGULATION OF CONTRACTILITY | 1998年 / 853卷
关键词
D O I
10.1111/j.1749-6632.1998.tb08305.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:380 / 392
页数:13
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