Abstract
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.
Highlights
Calcium-activated neutral proteases (CANPs) were discovered in 1964 by Guroff [1], but in 1980Murachi changed their name to calpain, as a contraction of calpain and papain, and coined the name calpastatin for their endogenous inhibitor [2]
What we found turned out to be quite remarkable: in short, our studies revealed that calpain-1 and calpain-2 play opposite functions in the brain, with calpain-1 activation being required for triggering certain forms of synaptic plasticity and thereby in various forms of learning and memory; in addition, calpain-1 is neuroprotective both during postnatal development and in adulthood
The results obtained with calpain inhibitors or the calpain-4 KO mice were further confirmed by experiments showing that calpain-1 KO mice were impaired in Theta burst stimulation (TBS)-long-term potentiation (LTP) and in hippocampus-dependent learning [6], clearly indicating that calpain-1 activation following synaptic NMDA receptor stimulation is essential for theta burst stimulation-induced LTP in field CA1 of the hippocampus
Summary
Calcium-activated neutral proteases (CANPs) were discovered in 1964 by Guroff [1], but in 1980. We initially proposed in 1984 that calpain played a critical role in long-term potentiation (LTP) and learning and memory [3] This hypothesis was recently validated by studies performed first in hippocampal slices from calpain-4 knock-out (KO) mice [4] and later in slices from calpain-1 KO mice [5,6]. In vitro biochemical studies suggested the major difference consisted in their calcium requirement for activation, with calpain-1 requiring micromolar calcium concentrations and calpain-2 millimolar calcium concentrations [2] This presented a significant challenge to study the potential role of calpain-2 in the brain, as such a high calcium requirement for calpain-2 activation made it unlikely that cytoplasmic calpain-2 could be activated under physiological and most pathological conditions. These different functions of calpain-1 and calpain-2 and the signaling pathways they regulate to perform these functions will be discussed in greater details in this review
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