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Originally published In Press as doi:10.1074/jbc.M212255200 on February 7, 2003

J. Biol. Chem., Vol. 278, Issue 16, 14162-14167, April 18, 2003
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Cross-talk between Calpain and Caspase Proteolytic Systems During Neuronal Apoptosis*

Robert W. NeumarDagger §, Y. Anne XuDagger , Hemal GadaDagger , Rodney P. Guttmann, and Robert Siman||

From the Departments of Dagger  Emergency Medicine and || Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and the  University of Kentucky Center on Aging, Lexington, Kentucky 40536

Cross-talk between calpain and caspase proteolytic systems has complicated efforts to determine their distinct roles in apoptotic cell death. This study examined the effect of overexpressing calpastatin, the specific endogenous calpain inhibitor, on the activity of the two proteolytic systems following an apoptotic stimulus. Human SH-SY5Y neuroblastoma cells were stably transfected with full-length human calpastatin cDNA resulting in 20-fold overexpression based on Western blot and 5-fold greater calpain inhibitory activity in cell extracts. Wild type and calpastatin overexpressing (CST1) cells were neuronally differentiated and apoptosis-induced with staurosporine (0.1-1.0 µM). Calpastatin overexpression decreased calpain activation, increased caspase-3-like activity, and accelerated the appearance of apoptotic nuclear morphology. Following 0.1-0.2 µM staurosporine, plasma membrane integrity based on calcein-acetoxymethyl fluorescence was significantly greater at 24 h in differentiated CST1 compared with differentiated wild type cells. However, this protective effect was lost at higher staurosporine doses (0.5-1.0 µM), which resulted in pronounced caspase-mediated degradation of the overexpressed calpastatin. These results suggest a dual role for calpains during neuronal apoptosis. In the early execution phase, calpain down-regulates caspase-3-like activity and slows progression of apoptotic nuclear morphology. Subsequent calpain activity, facilitated by caspase-mediated degradation of calpastatin, contributes to plasma membrane disruption and secondary necrosis.

* This study was supported by grants from the American Heart Association (9951263U), the W. W. Smith Foundation (H9902), and the Emergency Medicine Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Dept. of Emergency Medicine, Hospital of University of Pennsylvania, Ground Floor, Ravdin Bldg., 3400 Spruce St., Philadelphia, PA 19104-4283. Tel.: 215-898-4960; Fax: 215-573-5140; E-mail: rneumar@mail.med.upenn.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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