While the calpain system has now been discovered for over 50 years, there is still a paucity
of information regarding the organization and functions of the signaling pathways regulated by
these proteases, although calpains play critical roles in many cell functions. Moreover, calpain
overactivation has been shown to be involved in numerous diseases. Among the 15 calpain isoforms
identified, calpain-1 (aka μ-calpain) and calpain-2 (aka m-calpain) are ubiquitously distributed in
most 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 synaptic
plasticity and neuroprotection (Dr. Jekill), and calpain-2 limiting the extent of plasticity and
being neurodegenerative (Mr. Hyde). Calpain-mediated cleavage has been observed in cytoskeleton
proteins, membrane-associated proteins, receptors/channels, scaffolding/anchoring proteins, and
protein kinases and phosphatases. This review will focus on the signaling pathways related to local
protein synthesis, cytoskeleton regulation and neuronal survival/death regulated by calpain-1 and
calpain-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 regulators
of these 2 calpain isoforms.