Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death

Calpains are a family of soluble calcium-dependent proteases that are involved in multiple regulatory pathways. Our laboratory has focused on the understanding of the functions of two ubiquitous calpain isoforms, calpain-1 and calpain-2, in the brain. Results obtained over the last 30 years led to t...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2020-12, Vol.9 (12), p.2698
Main Authors: Wang, Yubin, Liu, Yan, Bi, Xiaoning, Baudry, Michel
Format: Article
Language:English
Subjects:
Animals
Brain - pathology
Calcium
Calpain
Calpain - metabolism
Cell Death
Gene expression
hippocampus
Humans
Hypotheses
Isoforms
Kinases
Learning
Mutation
Neurodegeneration
Neuronal Plasticity
Neurons - enzymology
Neurons - pathology
Neuroprotection
Physiology
Postsynaptic density proteins
Proteins
Review
signaling pathways
Synaptic plasticity
Traumatic brain injury
Zonula occludens-1 protein
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Summary:Calpains are a family of soluble calcium-dependent proteases that are involved in multiple regulatory pathways. Our laboratory has focused on the understanding of the functions of two ubiquitous calpain isoforms, calpain-1 and calpain-2, in the brain. Results obtained over the last 30 years led to the remarkable conclusion that these two calpain isoforms exhibit opposite functions in the brain. Calpain-1 activation is required for certain forms of synaptic plasticity and corresponding types of learning and memory, while calpain-2 activation limits the extent of plasticity and learning. Calpain-1 is neuroprotective both during postnatal development and in adulthood, while calpain-2 is neurodegenerative. Several key protein targets participating in these opposite functions have been identified and linked to known pathways involved in synaptic plasticity and neuroprotection/neurodegeneration. We have proposed the hypothesis that the existence of different PDZ (PSD-95, DLG and ZO-1) binding domains in the C-terminal of calpain-1 and calpain-2 is responsible for their association with different signaling pathways and thereby their different functions. Results with calpain-2 knock-out mice or with mice treated with a selective calpain-2 inhibitor indicate that calpain-2 is a potential therapeutic target in various forms of neurodegeneration, including traumatic brain injury and repeated concussions.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells9122698