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• W2080268439 abstract "Calpain-mediated cleavage of neuronal targets has long been associated with excitotoxicity and synaptic plasticity. In this issue of Neuron, two papers by Xu et al. and Abe and Takeichi explore the respective roles of mGluR1α cleavage in excitotoxicity and β-catenin cleavage in transcriptional control. Together, these papers show the functional importance of fragments of calpain-mediated cleavage. Calpain-mediated cleavage of neuronal targets has long been associated with excitotoxicity and synaptic plasticity. In this issue of Neuron, two papers by Xu et al. and Abe and Takeichi explore the respective roles of mGluR1α cleavage in excitotoxicity and β-catenin cleavage in transcriptional control. Together, these papers show the functional importance of fragments of calpain-mediated cleavage. Calpain, sometimes referred to as calcium-activated neutral protease, is among the most enigmatic proteases in the body and particularly the nervous system (Wu and Lynch, 2006Wu H. Lynch D.R. Mol. Neurobiol. 2006; 33: 215-236Crossref PubMed Scopus (121) Google Scholar). This family of proteases is recognized by their requirement for calcium and defined by specific inhibitors, but their substrate specificity defies complete classification. Calpain cleaves at preferred sequences in association with preferred tertiary structures of substrates, but without known absolute rules. Unlike most proteases, substrates of calpain are not usually destroyed but instead become dysregulated. Perhaps because of this unusual specificity, these enzymes have been associated with a diverse set of cellular functions inside and outside the nervous system. In neurons, spectrin has been defined as the prototypic substrate for calpain, inadvertently promoting the idea that the main function of calpain is structural modification. However, calpain has been associated with a variety of other cellular events, from cell adherence and cell division to transcriptional regulation and long-term potentiation (LTP). While calpain is clearly involved in these processes, the exact substrates and mechanisms by which calpain mediates its effects have been more difficult to elucidate. In this issue of Neuron, two articles link calpain-mediated cleavage of specific substrates to physiological and pathophysiological events in the nervous system. The first (Xu et al., 2007Xu W. Wong T.P. Chery N. Gaertner T. Wang Y.T. Baudry M. Neuron. 2007; 53 (this issue): 399-412Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar) investigates the known association of calpain with NMDA-receptor-mediated excitotoxicity. In this work, they show that calpain-mediated cleavage of mGluR1α creates functional receptors that enhance NMDA-induced excitotoxicity. Moreover, blocking calpain-mediated cleavage of mGluR1α with a fusion peptide containing the calpain-sensitive portion of the receptor protects neurons from excitotoxicity in vitro and in vivo. This deleterious effect of cleaved receptors may reflect their dissociation from the neuroprotective PI3K-Akt pathway, which in turn would enhance toxicity arising from NMDA receptor overstimulation. Such work thus provides a specific calpain-mediated pathway contributing to early steps in excitotoxicity, not simply the later structural changes frequently attributed to calpain in excitotoxic models (Wu and Lynch, 2006Wu H. Lynch D.R. Mol. Neurobiol. 2006; 33: 215-236Crossref PubMed Scopus (121) Google Scholar). While the present work shows the importance of this pathway, calpain also probably regulates excitotoxicity and PI3K through other substrates (Figure 1). The sodium/calcium exchanger is cleaved by calpain in a manner leading to its destruction (Bano et al., 2005Bano D. Young K.W. Guerin C.J. Lefeuvre R. Rothwell N.J. Naldini L. Rizzuto R. Carafoli E. Nicotera P. Cell. 2005; 120: 275-285Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar), leaving neurons unable to handle the calcium overload from NMDA receptor activation. In addition, the NR2B subunit of NR1/2B receptors is also a calpain substrate in neurons (Simpkins et al., 2003Simpkins K. Guttmann R.P. Dong Y. Chen Z. Sokol S. Neumar R.W. Lynch D.R. J. Neurosci. 2003; 23: 11322-11331Crossref PubMed Google Scholar). Interestingly, it is cleaved in a location that separates the channel of the receptor from the residues involved in NMDA-receptor-mediated PI3K activation (Waxman and Lynch, 2005Waxman E.A. Lynch D.R. J. Biol. Chem. 2005; 280: 29322-29333Crossref PubMed Scopus (63) Google Scholar). Whether this is toxic (by loss of PI3K activation) or protective (if PI3K were to become autonomously active) is difficult to ascertain. Similarly, a variety of other synaptic substrates are cleaved with a mixture of proposed protective and toxic roles (Wu and Lynch, 2006Wu H. Lynch D.R. Mol. Neurobiol. 2006; 33: 215-236Crossref PubMed Scopus (121) Google Scholar). Global inhibition of calpain might thus be hard to utilize as a potential therapeutic intervention in the early phases of excitotoxicity. The present study provides a paradigm for interpreting the role of calpain-mediated mGluR cleavage specifically in excitotoxic therapy and a rationale for developing substrate-selective approaches (such as the fusion protein used here) for modulating calpain. In contrast, the second work (Abe and Takeichi, 2007Abe K. Takeichi M. Neuron. 2007; 53 (this issue): 387-397Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar) takes calpain from a local mediator to a modulator of defined signaling pathways controlling transcription. β-catenins are transcriptional modulators involved in variety of cellular events, including carcinogenesis and development. In the present work, the authors demonstrate that NMDA-receptor-activated calpain cleaves β-catenins into stable fragments in neurons. Such fragments become resistant to GSK3β-mediated proteolysis, undergo nuclear translocation, and modulate transcription of specific genes controlled by the transcription factor Tcf. Furthermore, not only is this pathway activated under potentially excitotoxic conditions but also in rats undergoing exploratory behavior, linking calpain to genetic control of neuronal plasticity. Though not the first example of genetic regulation based on calpain-mediated cleavage (IκBα and calcineurin also alter transcription following calpain-mediated cleavage) (Wu and Lynch, 2006Wu H. Lynch D.R. Mol. Neurobiol. 2006; 33: 215-236Crossref PubMed Scopus (121) Google Scholar, Shumway et al., 1999Shumway S.D. Maki M. Miyamoto S. J. Biol. Chem. 1999; 274: 30874-30881Crossref PubMed Scopus (159) Google Scholar), this paper provides further evidence that the calpain system is not only a destructive system but also an essential component of ongoing activity in the nervous system. How do these studies aid in the conceptual understanding of the calpain system and how it may be manipulated? At first glance these results provide further evidence of the diversity of calpain substrates but no easy way to conceptualize the role of calpain based on substrate specificity. However, these papers provide considerable insight into the functional role of calpain-mediated proteolysis as a regulatory mechanism capable of signaling in local fashion at synapses and to nuclear targets. Future work in understanding the regulatory role of calpain thus might concentrate not on definition of targets alone but also regulation of these targets. For example, the fusion protein controlling mGluR cleavage appears to be selectively directed to NMDA-receptor-activated calpain at the synapse by mechanisms that are not yet clear (Xu et al., 2007Xu W. Wong T.P. Chery N. Gaertner T. Wang Y.T. Baudry M. Neuron. 2007; 53 (this issue): 399-412Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). Two important concepts that emerge as regulatory mechanisms involve control of substrate specificity by phosphorylation and of calpain activity itself by the balance with its endogenous inhibitor calpastatin (Wu and Lynch, 2006Wu H. Lynch D.R. Mol. Neurobiol. 2006; 33: 215-236Crossref PubMed Scopus (121) Google Scholar, Cuevas et al., 2003Cuevas B.D. Abell A.N. Witowsky J.A. Yujiri T. Johnson N.L. Kesavan K. Ware M. Jones P.L. Weed S.A. DeBiasi R.L. et al.EMBO J. 2003; 22: 3346-3355Crossref PubMed Scopus (107) Google Scholar, Sawhney et al., 2006Sawhney R.S. Cookson M.M. Omar Y. Hauser J. Brattain M.G. J. Biol. Chem. 2006; 281: 8497-8510Crossref PubMed Scopus (93) Google Scholar). In focal adhesion, activity of calpain and its targeting to specific substrates involves formation of a macromolecular complex involving calpain, ERK, Src, and the target integrins. Perhaps synapses use similar mechanisms for directing calpain to relevant substrates. Finally, the present studies also raise the question of whether other regulatory proteases not yet discovered exist in the nervous system. Although NR1 of the NMDA receptor is not normally a calpain substrate in neurons, some studies have suggested that its C terminus can undergo nuclear translocation (Wu and Lynch, 2006Wu H. Lynch D.R. Mol. Neurobiol. 2006; 33: 215-236Crossref PubMed Scopus (121) Google Scholar, Bradley et al., 2006Bradley J. Carter S.R. Rao V.R. Wang J. Finkbeiner S. J. Neurosci. 2006; 26: 1065-1076Crossref PubMed Scopus (55) Google Scholar). Similarly, the C termini of various voltage-gated calcium channels can be cleaved and translocated to the nucleus (Gomez-Ospina et al., 2006Gomez-Ospina N. Tsuruta F. Barreto-Chang O. Hu L. Dolmetsch R. Cell. 2006; 127: 591-606Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, Kordasiewicz et al., 2006Kordasiewicz H.B. Thompson R.M. Clark H.B. Gomez C.M. Hum. Mol. Genet. 2006; 15: 1587-1599Crossref PubMed Scopus (104) Google Scholar), where they can act as transcription factors (Gomez-Ospina et al., 2006Gomez-Ospina N. Tsuruta F. Barreto-Chang O. Hu L. Dolmetsch R. Cell. 2006; 127: 591-606Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). Such a process may be involved in the pathogenesis of spinocerebellar ataxia type 6. While it is suspected that calpain may be involved, direct evidence for a role for calpain is lacking. Consequently, the concept of proteolysis as a regulatory rather than destructive mechanism may exist even beyond the calpain system. Calpain-Mediated mGluR1α Truncation: A Key Step in ExcitotoxicityXu et al.NeuronFebruary 01, 2007In BriefExcitotoxicity mediated by glutamate receptors plays crucial roles in ischemia and other neurodegenerative diseases. Whereas overactivation of ionotropic glutamate receptors is neurotoxic, the role of metabotropic glutamate receptors (mGluRs), and especially mGluR1, remains equivocal. Here we report that activation of NMDA receptors results in calpain-mediated truncation of the C-terminal domain of mGluR1α at Ser936. The truncated mGluR1α maintains its ability to increase cytosolic calcium while it no longer activates the neuroprotective PI3K-Akt signaling pathways. Full-Text PDF Open ArchiveNMDA-Receptor Activation Induces Calpain-Mediated β-Catenin Cleavages for Triggering Gene ExpressionAbe et al.NeuronFebruary 01, 2007In BriefThe canonical Wnt-β-catenin signaling pathway is important for a variety of developmental phenomena as well as for carcinogenesis. Here, we show that, in hippocampal neurons, NMDA-receptor-dependent activation of calpain induced the cleavage of β-catenin at the N terminus, generating stable, truncated forms. These β-catenin fragments accumulated in the nucleus and induced Tcf/Lef-dependent gene transcription. We identified Fosl1, one of the immediate-early genes, as a target of this signaling pathway. Full-Text PDF Open Archive" @default.
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• W2080268439 title "Picking Up the Pieces: The Roles of Functional Remnants of Calpain-Mediated Proteolysis" @default.
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• W2080268439 doi "https://doi.org/10.1016/j.neuron.2007.01.014" @default.
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