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Updated: May 22, 2026
Pull-down of Calmodulin-binding Proteins
Published on: January 23, 2012
High molecular weight calmodulin-binding protein: 20 years onwards-a potential therapeutic calpain inhibitor
Sreejit Parameswaran1, Rajendra K Sharma
1Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
Abstract:
Apoptosis in cardiovascular diseases is considered to be a major reason for heart failure. Caspase-independent apoptosis due to calpains and other proteases occurs due to increase in intracellular Ca(2+) levels which act on a feed-forward mechanism. Calpains are Ca(2+)-activated cysteine proteases present in the cytosol as inactive proenzymes. Calpastatin is most efficient and specific calpain inhibitor present in vivo. Earlier, we had reported the expression of novel high molecular weight calmodulin-binding protein (HMWCaMBP) in human and animal cardiac tissue and in very minute quantities in brains and lungs. HMWCaMBP showed calpastatin activity and was also found to be highly homologous to calpastatin I and calpastatin II. Decreased expression of HMWCaMBP was observed during ischemia as it is susceptible to proteolysis by calpains during ischemia-reperfusion. In normal myocardium, HMWCaMBP may protect its substrate from calpains. However, during an early stage of ischemia/reperfusion due to increased Ca(2+) influx, calpain activity often exceeds HMWCaMBP activity. This leads to proteolysis of HMWCaMBP and other protein substrates, resulting in cellular damage. The role of HMWCaMBP in ischemia/reperfusion is yet to be elucidated. The present review summarizes the developments in area of HMWCaMBP from the authors' laboratory and its potential for therapy.
Insights
Cardiovascular diseases involve apoptosis, a key factor in heart failure. A novel protein, high molecular weight calmodulin-binding protein (HMWCaMBP), shows promise in protecting heart tissue from damage during ischemia.
Area of Science:
- Cardiovascular Biology
- Cellular Proteolysis
- Apoptosis Mechanisms
Background:
- Apoptosis contributes significantly to heart failure in cardiovascular diseases.
- Caspase-independent apoptosis, mediated by calpains and other proteases, is triggered by elevated intracellular Ca(2+) levels.
- Calpains are Ca(2+)-activated cysteine proteases, and calpastatin is their specific inhibitor.
Purpose of the Study:
- To review the role of a novel high molecular weight calmodulin-binding protein (HMWCaMBP) in cardiovascular health.
- To elucidate the function of HMWCaMBP in ischemia-reperfusion injury.
- To explore the therapeutic potential of HMWCaMBP.
Main Methods:
- Previous research identified HMWCaMBP in cardiac tissue, showing homology to calpastatins and calpastatin activity.
- Studies observed decreased HMWCaMBP expression during ischemia due to its susceptibility to calpain proteolysis.
- Analysis of HMWCaMBP's interaction with calpains and its protective role in normal myocardium.
Main Results:
- HMWCaMBP exhibits calpastatin activity and homology to known calpastatins.
- Ischemia-reperfusion leads to increased calpain activity, overwhelming HMWCaMBP and causing proteolysis of HMWCaMBP and other substrates.
- This proteolysis results in cellular damage, highlighting the detrimental effects of imbalanced calpain/HMWCaMBP activity.
Conclusions:
- HMWCaMBP may play a protective role against calpain-mediated damage in normal cardiac tissue.
- During ischemia-reperfusion, calpain activity can exceed HMWCaMBP's inhibitory capacity, leading to cellular injury.
- Further research is needed to fully understand HMWCaMBP's role and its therapeutic implications in ischemia-reperfusion.
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