Calpain 1

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Introduction

Each cell in multicellular organisms must perform many basic functions, including growth, reproduction, migration, response to external stimuli, and survival or death. Neurons have all functions except replication, and face an additional challenge, that is, they need to better respond and adapt to various internal and external signals. Therefore, the plasticity of neurons and synapses, the ability of neurons or synapses to adapt to environmental changes, and neuronal survival or death, are processes that have evolved in parallel using the cellular machinery involved in basic cellular physiological functions. Calpains are an old family of neutral, soluble, and calcium-dependent proteases, which have the unique property of using protein cleavage to modify the activity of their substrate proteins. In this way, they constitute a post-translational regulatory mechanism, which is irreversible and lasting. Numerous studies have shown that the two major calpain isoforms in the brain, calpain 1 and calpain 2, play opposite roles in synaptic plasticity and neuronal survival/ neurodegeneration.

Localization of calpain within mitochondria

Calpain is a cytoplasmic enzyme, but studies have shown that calpain is also present in mitochondria. Calpain 1 has been identified in the mitochondria and is involved in the cleavage of apoptosis-inducing factor (AIF). The N-terminus of the large subunit of calpain 1 contains a mitochondrial leader sequence, and its small subunit can be imported into mitochondria together with the corresponding large subunit. The biochemical characteristics of mitochondrial calpain 1 are similar to cytosolic calpain 1 with an 80 kDa large catalytic subunit and a 28 kDa small regulatory subunit-calpain 4. In liver mitochondria, calpain 2 is found in intermembrane space (IMS). The activation of mitochondrial calpain 2 increases the permeability of outer membrane (OMM) by interacting with voltage dependent anion channel (VDAC) in liver mitochondria. Calpain 2 is also found in the mitochondria of the hippocampus, cerebellum, and cortex. However, the presence of calpain 2 was hardly detected in heart mitochondria purified by trypsin. Calpain 10 is another mitochondrial localized calpain involved in calcium-induced mitochondrial dysfunction. In renal cortex mitochondria, calpain 10 is present in the outer membrane, intermembrane space, inner membrane, and matrix. Calpain 10 is also present in heart mitochondria. The activation of calpain 10 increases cell damage by disrupting the mitochondrial respiratory chain, and also participates in the disruption of ryanodine receptor- mediated apoptosis.

Role of calpains in synaptic plasticity: implications for learning and memory

Calpains are essential for long-term potentiation (LTP) and memory formation. Early studies using broad specific protease inhibitors provided the first evidence to support this hypothesis. These results were later confirmed using genetic manipulation, where specific silencing or deletion of calpain 1 or inactivation of two calpain isoforms in the brain can impair LTP and certain learning functions. Nevertheless, the exact molecular mechanism of calpain targets related to synaptic plasticity regulated by calpain is still unclear until today. Through calpain 2 mediated mTOR activation and de novo protein synthesis, synaptic SCOP levels quickly recovered, restored the basic level of ERK phosphorylation. Many recent studies have shown that this mechanism can operate various forms of memory, such as fear conditioning and object recognition. Therefore, as shown in Figure 5, the current model of LTP regulation by calpains can be divided into two different phases. First, during the LTP induction process, activation calpain 1 by calcium enters through the NMDA receptor triggers the degradation of spectrin and other cytoskeletal proteins, and at the same time stimulates ERK activation through SCOP degradation, which serves to phosphorylate several downstream proteins including AMPA receptors, thereby favoring their synaptic recruitment (Figure 1).

Figure 1. Schematic representation of the crosstalk between protein synthesis and cytoskeletal reorganization during synaptic plasticity (Briz, V.; Baudry, M. 2016)

In the second phase, calpain 2 activity stimulated and the Akt/mTOR signaling cascade initiated by TrkB receptor activation with important roles during the consolidation phase (Figure 2). Therefore, the model assumes that the activities of plasticin 1 and 2 are well regulated in a spatiotemporal manner during plasticity events, which is likely to be achieved by association with selective scaffold protein complexes.

Figure 2. Schematic summary of the roles of calpain in synaptic plasticity (Briz, V.; Baudry, M. 2016)