Targeting calpain in synaptic plasticity

Abstract

Introduction: Calpains represent a family of neutral, calcium-dependent proteases, which modify the function of their target proteins by partial truncation. These proteases have been implicated in numerous cell functions, including cell division, proliferation, migration, and death. In the CNS, where µ-calpain and m-calpain are the main calpain isoforms, their activation has been linked to synaptic plasticity as well as to neurodegeneration. This review will focus on the role of calpains in synaptic plasticity and discuss the possibility of developing methods to manipulate calpain activity for therapeutic purposes.

Areas covered: This review covers the literature showing how calpains are implicated in synaptic plasticity and in a number of conditions associated with learning impairment. The possibility of developing new drugs targeting these enzymes for treating these conditions is discussed.

Expert opinion: As evidence accumulates that calpain activation participates in neurodegeneration and cancer, there is interest in developing therapeutic approaches using direct or indirect calpain inhibition. In particular, a peptide derived from the calpain truncation site of mGluR1α was shown to decrease neurodegeneration following neonatal hypoxia/ischemia. More selective approaches need to be developed to target calpain or some of its substrates for therapeutic indications associated with deregulation of synaptic plasticity.

Figure 1. Schematic structure of a mammalian μ- or m-calpain

μ- and m-calpains are heterodimeric proteins, which share a common small regulatory subunit (calpain-S1, a.k.a. calpain-4, 30 kDa) and differ in the large catalytic subunit (calpain-1 and calpain-2, respectively; 80 kDa). Two domain nomenclature systems are presented here: domain numbers (I – VI) and descriptive acronyms. N, the N-terminal anchor helix region of the large subunit; CysPc, the protease domain, comprising two protease core domains (PC1 and PC2); C2L, C2 domain-like domain; PEF(L), penta-EF-hand domain, L referring to large subunit; PEF(S), penta-EF-hand domain, S for small subunit; GR, the glycine-rich hydrophobic domain at the N-terminus of the small subunit.

Figure 2. Complex regulation of calpain activity by protein kinases and phosphatases

As discussed in the text, calpain is activated by ERK-mediated phosphorylation and inactivated by PP2A-mediated dephosphorylation. In addition, calpain is also inactivated by PKA-mediated phosphorylation. Considering the numerous cross-talks between various protein kinases and phosphatases, calpain is subjected to extremely complex regulation by phosphorylation/dephosphorylation reactions.

Figure 3. Multiple functions of calpain activation in various stages of LTP

Calpain can be activated by several signals: calcium influx from NMDA receptors, integrin activation, and BDNF→ TrkB→ ERK-mediated phosphorylation. Once activated, calpain can result in rapid modifications of glutamate receptors and synaptic structure; it can also participate in the regulation of dendritic spine cytoskeleton; finally, by regulating local protein synthesis and transcription factors, it can be involved in long-term consolidation.

Figure 4. Comparison of the roles of calpain in tumorigenesis and synaptic plasticity

By activating ubiquitously distributed cellular cascades participating in cell adhesion, migration, and cell morphogenesis, calpain activation can participate in a wide variety of basic cellular processes, including tumor formation and dissemination, as well as in neurite extension and synaptic plasticity.