Regulatory role of calpain in neuronal death

Abstract

Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and autophagic pathways are affected by calpain. Calpain plays a very important role in neuronal death and various neurological disorders. This review introduces recent research progress related to the regulatory mechanisms of calpain in neuronal death. Various neuronal programmed death pathways including apoptosis, autophagy and regulated necrosis can be divided into receptor interacting protein-dependent necroptosis, mitochondrial permeability transition-dependent necrosis, pyroptosis and poly (ADP-ribose) polymerase 1-mediated parthanatos. Calpains cleave series of key substrates that may lead to cell death or participate in cell death. Regarding the investigation of calpain-mediated programed cell death, it is necessary to identify specific inhibitors that inhibit calpain mediated neuronal death and nervous system diseases.

Keywords: B-cell lymphoma; apoptosis; autophagy; calpain; calpastatin; central nervous system; cyclin-dependent kinases; mitochondrial permeability transition; nerve regeneration; neural regeneration.

Figure 1

Hypothetical mechanisms of calpain in neuronal death.LAMP, Ataxin, and the complex of Beclin and Atg are activated by inactivated calpain, which inhibits autophagy. The inactivated complex of Beclin and Atg, induced by activated calpain, converts autophagy to apoptosis. Calpain is implicated in numerous steps during apoptosis, including the cleavage and activation of caspases, which lead to the release of cytochrome c and AIF. Hsp70 physiologically stabilizes AIF. Calpain also cleaves BCL 2 family members, including Bax and Bid, to promote apoptosis and promotes the formation of CDK5-P25 complex, which also promotes apoptosis. Except for AIF mediated apoptosis, AIF combined with H2AX, mediated by PARP-1, might lead to regulated necrosis. In addition, calpain cleaves a series of substrates, such as JNK-interacting protein-1, and activates proteins, including integrin and RIP-1, to promote necrosis.