Calpain-1 and Calpain-2 in the Brain: Dr. Jekill and Mr Hyde?

摘要

While the calpain system has now been discovered for over 50 years, there is still a pau-city of information regarding the organization and functions of the signaling pathways regulated bythese proteases, although calpains play critical roles in many cell functions. Moreover, calpainoveractivation has been shown to be involved in numerous diseases. Among the 15 calpain isoformsidentified, calpain-1 (aka μ-calpain) and calpain-2 (aka m-calpain) are ubiquitously distributed inmost tissues and organs, including the brain. We have recently proposed that calpain-1 and calpain-2 play opposite functions in the brain, with calpain-1 activation being required for triggering synap-tic plasticity and neuroprotection (Dr. Jekill), and calpain-2 limiting the extent of plasticity andbeing neurodegenerative (Mr. Hyde). Calpain-mediated cleavage has been observed in cytoskeletonproteins, membrane-associated proteins, receptors/channels, scaffolding/anchoring proteins, andprotein kinases and phosphatases. This review will focus on the signaling pathways related to localprotein synthesis, cytoskeleton regulation and neuronal survival/death regulated by calpain-1 andcalpain-2, in an attempt to explain the origin of the opposite functions of these 2 calpain isoforms.This will be followed by a discussion of the potential therapeutic applications of selective regulatorsof these 2 calpain isoforms.