Calpains: Master Regulators of Synaptic Plasticity

Briz, Victor; Baudry, Michel

doi:10.1177/1073858416649178

Cited by 46 publications

(44 citation statements)

References 70 publications

(116 reference statements)

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“…Studied intensively as models of learning and memory, the changes in synaptic function that accompany long-term potentiation and long-term depression require rapid, reversible changes in ion fluxes, protein localization and protein phosphorylation, as well as more lasting alterations in transcription and translation. In addition, limited proteolytic cleavage of synaptic proteins such as spectrin, MARCKS, and drebrin by calpains, neutral calcium-activated cysteine proteases, is essential for long-term potentiation involving GluN2B-containing receptors 21 .…”

Section: Introductionmentioning

confidence: 99%

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

Miller¹,

Yan²,

Machida³

et al. 2017

ACS Chem. Neurosci.

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Kalirin7 (Kal7), a postsynaptic Rho GDP/GTP exchange factor (RhoGEF), plays a crucial role in long term potentiation and in the effects of cocaine on behavior and spine morphology. The KALRN gene has been linked to schizophrenia and other disorders of synaptic function. Mass spectrometry was used to quantify phosphorylation at 26 sites in Kal7 from individual adult rat nucleus accumbens and prefrontal cortex before and after exposure to acute or chronic cocaine. Region- and isoform-specific phosphorylation was observed along with region-specific effects of cocaine on Kal7 phosphorylation. Evaluation of the functional significance of multi-site phosphorylation in a complex protein like Kalirin is difficult. With the identification of five tyrosine phosphorylation (pY) sites, a panel of 71 SH2 domains was screened, identifying subsets that interacted with multiple pY sites in Kal7. In addition to this type of reversible interaction, endoproteolytic cleavage by calpain plays an essential role in long-term potentiation. Calpain cleaved Kal7 at two sites, separating the N-terminal domain, which affects spine length, and the PDZ binding motif from the GEF domain. Mutations preventing phosphorylation did not affect calpain sensitivity or GEF activity; phosphomimetic mutations at specific sites altered protein stability, increased calpain sensitivity and reduced GEF activity.

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Section: Introductionmentioning

confidence: 99%

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

Miller¹,

Yan²,

Machida³

et al. 2017

ACS Chem. Neurosci.

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“…For longer forms of memory, calpains may function in synaptic remodeling through proteolytic cleavage of cytoskeletal elements (Briz and Baudry, 2016; Jourdi, 2014). It has also been hypothesized that calpain activity affects dendritic protein synthesis associated with synaptic plasticity (Briz and Baudry, 2016; Briz et al, 2013). In our preceding experiments, although both calpeptin and MDL-28170 are reversible in vivo these inhibitors likely retain some efficacy during the molecular consolidation phase of LFI memory even though the inhibitors were injected prior to training.…”

Section: Resultsmentioning

confidence: 99%

“…At least 14 calpain isoforms and multiple splice variants have been identified in humans (Doshi and Lynch, 2009; Franco and Huttenlocher, 2005; Paquet-Durand et al, 2007; Suzuki et al, 2004; Ueyama et al, 1998; Wu and Lynch, 2006) with calpain-1 and calpain-2 the primary isoforms found in neurons (Baudry and Bi, 2016; Baudry et al, 2013; Briz and Baudry, 2016). Calpain-1 is more sensitive to calcium with in vitro activation occurring at micromolar concentrations while calpain-2 requires near millimolar concentrations of calcium for activation (Baudry and Bi, 2016; Jourdi, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…More recently, calpains have been suggested to be critical regulators for numerous brain functions including neuronal migration, neuronal differentiation, neuroprotection and synaptic plasticity (Briz and Baudry, 2016; Tan et al, 2006). Excessive or deregulated calpain activation is associated with ischemic cell death, neurodegenerative diseases including Alzheimer’s disease (Cho et al, 2015), and pathological necrosis (Paquet-Durand et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Differential role of calpain-dependent protein cleavage in intermediate and long-term operant memory in Aplysia

Lyons

Gardner

Lentsch

et al. 2017

Neurobiology of Learning and Memory

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In addition to protein synthesis, protein degradation or protein cleavage may be necessary for intermediate (ITM) and long-term memory (LTM) to remove molecular constraints, facilitate persistent kinase activity and modulate synaptic plasticity. Calpains, a family of conserved calcium dependent cysteine proteases, modulate synaptic function through protein cleavage. We used the marine mollusk Aplysia californica to investigate the in vivo role of calpains during intermediate and long-term operant memory formation using the learning that food is inedible (LFI) paradigm. A single LFI training session, in which the animal associates a specific netted seaweed with the failure to swallow, generates short (30 min), intermediate (4–6 hr) and long-term (24 hr) memory. Using the calpain inhibitors calpeptin and MDL-28170, we found that ITM requires calpain activity for induction and consolidation similar to the previously reported requirements for persistent protein kinase C activity in intermediate-term LFI memory. The induction of LTM also required calpain activity. In contrast to ITM, calpain activity was not necessary for the molecular consolidation of LTM. Surprisingly, six hours after LFI training we found that calpain activity was necessary for LTM, although this is a time at which neither persistent PKC activity nor protein synthesis is required for the maintenance of long-term LFI memory. These results demonstrate that calpains function in multiple roles in vivo during associative memory formation.

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“…Calpains are proteases responsible for the degradation of several cytoskeletal elements (Briz and Baudry 2016) and have been associated with motility and the acrosome reaction (Aoyama et al 2001;Ozaki et al 2001;Ben-Aharon et al 2005), because during capacitation, calpain inhibition blocks motility and the acrosome reaction. We have shown that, by inhibiting spectrin cytoskeleton cleavage via calpain, the normal course of the acrosome reaction is blocked in guinea pig sperm (Bastian et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Calpain inhibition prevents flotillin re-ordering and Src family activation during capacitation

et al. 2017

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Prior to fertilization, mammalian sperm undergo several molecular, biochemical and physiological changes in a process termed capacitation. However, the mechanisms explaining the involvement of cytoskeletal remodeling and membrane re-ordering in each process prior to fertilization remain poorly understood. We found that the migration of both flotillin microdomains and Src family kinases towards the apical ridge of guinea pig sperm occurs under capacitating conditions. This re-ordering is associated with spectrin cleavage by calpain. Moreover, Src, Fyn, Lyn and Hck interact with flotillin-1; this interaction increases in a capacitation-dependent manner and the increased autophosphorylation of these kinases is linked to flotillin-1 association. The aforementioned results are prevented by the inhibition of calpain by calpeptin. Thus, spectrin cytoskeleton cleavage during capacitation seems to precede the reorganization of flotillin microdomains and Src family kinases towards the apical ridge of the sperm head in order to initiate the signaling cascade required for proper capacitation and further acrosome reaction. The significance of the Src family kinase reorganization for capacitation is demonstrated by the inhibition of calpain during capacitation also preventing the Src-family-kinase-dependent phosphorylation of FAK at Tyr576/577. Our work further highlights the scaffolding properties of flotillin microdomains and reveals the importance of their large-scale segregation during capacitation.

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Calpains: Master Regulators of Synaptic Plasticity

Cited by 46 publications

References 70 publications

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

Differential role of calpain-dependent protein cleavage in intermediate and long-term operant memory in Aplysia

Calpain inhibition prevents flotillin re-ordering and Src family activation during capacitation

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