Mechanistic Role of Calpains in Postischemic Neurodegeneration

Abstract

The calpain family of proteases is causally linked to postischemic neurodegeneration. However, the precise mechanisms by which calpains contribute to postischemic neuronal death have not been fully elucidated. This review outlines the key features of the calpain system, and the evidence for its causal role in postischemic neuronal pathology. Furthermore, the consequences of specific calpain substrate cleavage at various subcellular locations are explored. Calpain substrates within synapses, plasma membrane, endoplasmic reticulum, lysosomes, mitochondria, and the nucleus, as well as the overall effect of postischemic calpain activity on calcium regulation and cell death signaling are considered. Finally, potential pathways for calpain-mediated neurodegeneration are outlined in an effort to guide future studies aimed at understanding the downstream pathology of postischemic calpain activity and identifying optimal therapeutic strategies.

Calpain-cleaved Type 1 Inositol 1,4,5-Trisphosphate Receptor (InsP3R1) Has InsP3-independent Gating and Disrupts Intracellular Ca2+ Homeostasis

“…2) targeting the new amino terminus of InsP 3 R1 after calpain proteolysis provides a useful tool for studying the truncated form of the channel in multiple species, including human. 3 To begin characterizing the functional consequences of calpain proteolysis of InsP 3 R1, we utilized a recombinant channel construct corresponding to the 95-kDa carboxyl-terminal fragment of InsP 3 R1 produced by calpain cleavage (Fig. 3).…”

“…Cells deficient in InsP 3 Rs are resistant to apoptosis (4,5) suggesting that InsP 3 R-mediated Ca 2ϩ signaling plays a mechanistic role in cell death. Altered InsP 3 R channel function induces aberrant neuronal Ca 2ϩ signaling in a variety of neurodegenerative diseases including Alzheimer disease (6,7), Huntington disease (8), and ischemia (9).…”

“…Conversely, disrupted [Ca 2ϩ ] i can serve as a trigger for cell death (1,2). In particular, compelling evidence suggests that disruption of cellular Ca 2ϩ homeostasis, caused in part by dysfunction of Ca 2ϩ regulatory proteins, plays a causal role in both acute brain injury and chronic neurodegenerative diseases (3).…”

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…Moreover, extrasynaptic NMDAR activity induces calpainmediated cleavage of Myocyte enhancer factor 2 (MEF2), glutamic acid decarboxylase (GAD65/67), Fodrin, NCX3, and STEP (Xu et al, 2009a,b;Monnerie et al, 2010;Wei et al, 2012). activation of calpains by the intracellular calcium overload in brain ischemia and in excitotoxic conditions (Camins et al, 2006;Bevers and Neumar, 2008) leads to the cleavage of plasma membrane proteins (Lu et al, 2000;Neumar et al, 2001;Rong et al, 2001;Yuen et al, 2007;Gomes et al, 2012), synaptic vesicle proteins Lobo et al, 2011), transporters (Bano et al, 2005;Pottorf et al, 2006), mitochondrial proteins (Takano et al, 2005) and many other substrates (Bevers and Neumar, 2008). Lipases are also activated by calcium, further increasing the production of free radical species (Farooqui and Horrocks, 1994).…”

Calpains mediate epithelial-cell death during mammary gland involution: mitochondria and lysosomal destabilization

“…Consequently, the hydrolytic enzymes typically sequestered within lysosomes, primarily the cathepsins, are released into the cytosol. 20 Focusing on mammary gland involution, we should point out that calcium concentration increases in mammary tissue during weaning 21 and this could have a pivotal role in apoptosis 13 and mammary gland remodeling. Therefore, it is likely that CAPNs become activated during post-lactational regression.…”