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

Abstract

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.

Keywords: Calpain; learning; neurodegeneration; neuroprotection; signaling pathways; synaptic plasticity..

Fig. (1)

Comparison of the catalytic sites of calpain-1 and calpain-2. A. Amino acid sequences of the catalytic sites of calpain-1 and calpain-2. Calpain-1: PDB: 2ARY_B. Calpain-2: GenBank: EAW93251.1. Identical amino acids are highlighted and amount for more than 75% of the sequences. B. Protein backbones shown in surface mode with blue color indicating identical residues and red color non-identical residues. A ketoamide ligand is shown bound to the catalytic site. From [56]. (The color version of the figure is available in the electronic copy of the article).

Fig. (2)

Schematic representation of some of the signaling pathways regulated by calpain-1 and calpain-2. Calpain-1 is downstream of the synaptic NMDA receptors and its activation following NMDA receptor stimulation results in the cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and the activation of the Akt and Extracellular signal Regulated Kinase (ERK) pathways, which are responsible for linking calpain-1 to synaptic plasticity and to neuroprotection. On the other hand, calpain-2 is downstream of the extrasynaptic NMDA receptors, and its activation leads to the cleavage of STEP and PTPN13, thus linking calpain-2 to neurodegeneration. In addition, calpain-2 cleaves PTEN, resulting in mTOR activation and placing a break on synaptic plasticity (modified from [2]). As discussed in the text, a selective calpain-1 activator or a selective calpain-2 inhibitor would enhance synaptic plasticity and stimulate neuroprotective mechanisms.