Pharmacology of the Cardiac Sarcoplasmic Reticulum Calcium ATPase-Phospholamban Interaction

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 hypothesiz...

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Bibliographic Details
Published in:Annals of the New York Academy of Sciences 1998-09, Vol.853 (1), p.380-392
Main Author: JOHNSON JR, ROBERT G.
Format: Article
Language:English
Subjects:
Animals
Calcium - metabolism
Calcium Channels - physiology
Calcium-Binding Proteins - metabolism
Calcium-Transporting ATPases - metabolism
Drug Design
Genetic Engineering
Heart - physiology
Heart - physiopathology
Heart Failure - drug therapy
Heart Failure - physiopathology
Humans
Mice
Models, Cardiovascular
Myocardium - metabolism
Sarcoplasmic Reticulum - metabolism
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Summary: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.
ISSN:0077-8923
1749-6632
DOI:10.1111/j.1749-6632.1998.tb08305.x