Premium
SERCA2a stimulation by istaroxime: a novel mechanism of action with translational implications
Author(s) -
Huang Christopher L H
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12288
Subject(s) - serca , stimulation , chemistry , cardiac function curve , electrophysiology , diastole , cardiac muscle , inhibitory postsynaptic potential , neuroscience , biophysics , heart failure , atpase , medicine , pharmacology , biology , biochemistry , enzyme , blood pressure
Sarcoplasmic reticular (SR) Ca(2+) -ATPase (SERCA2a) is central to cardiac electrophysiological and mechanical function. It ensures full diastolic relaxation minimizing delayed after-potentials that would otherwise compromise membrane electrophysiological stability, and optimizes SR Ca(2+) refilling and systolic contraction. Previous studies demonstrated that the small molecule agent istaroxime stimulates SERCA2a-ATPase activity, restoring its function in failing hearts, and enhancing indices of mechanical, and SR Ca(2+) release and re-uptake, activity. Ferrandi et al (2013) now elegantly demonstrate its ability to dissociate the phospholamdan (PB) bound to cardiac SERCA2a, thereby removing the inhibitory effect of PB on SERCA2a. This effect was independent of the cAMP/PKA system and modified a specific SERCA2a reaction step. They used SERCA-enriched SR preparations from a rigorously validated and realistic physiological, canine model of cardiac failure with established Na(+) -K(+) -ATPase sensitivity to cardiac glycosides and SR Ca(2+) handling features. These findings potentially translate into a novel management of the major and increasingly important public health challenge of chronic cardiac failure.