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

Author(s): Michel Baudry* .

Journal Name: Current Neuropharmacology

Volume 17 , Issue 9 , 2019

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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, signaling pathways, synaptic plasticity, learning, neurodegeneration, neuroprotection.

[1]
Guroff, G. A neutral, calcium-activated proteinase from the soluble fraction of rat brain. J. Biol. Chem., 1964, 239, 149-155.
[PMID: 14114836]
[2]
Mehendale, H.M.; Limaye, P.B. Calpain: A death protein that mediates progression of liver injury. Trends Pharmacol. Sci., 2005, 26(5), 232-236.
[http://dx.doi.org/10.1016/j.tips.2005.03.008] [PMID: 15860369]
[3]
Potz, B.A.; Abid, M.R.; Sellke, F.W. Role of calpain in pathogenesis of human disease processes. J. Nat. Sci., 2016, 2(9), e218.
[PMID: 27747292]
[4]
Baudry, M.; Bi, X. Calpain-1 and calpain-2: The Yin and Yang of synaptic plasticity and neurodegeneration. Trends Neurosci., 2016, 39(4), 235-245.
[http://dx.doi.org/10.1016/j.tins.2016.01.007] [PMID: 26874794]
[5]
Loane, D.J.; Byrnes, K.R. Role of microglia in neurotrauma. Neurotherapeutics, 2010, 7(4), 366-377.
[http://dx.doi.org/10.1016/j.nurt.2010.07.002] [PMID: 20880501]
[6]
Wang, Y.; Hall, R.A.; Lee, M.; Kamgar-Parsi, A.; Bi, X.; Baudry, M. The tyrosine phosphatase PTPN13/FAP-1 links calpain-2, TBI and tau tyrosine phosphorylation. Sci. Rep., 2017, 7(1), 11771.
[http://dx.doi.org/10.1038/s41598-017-12236-3] [PMID: 28924170]
[7]
Wang, Y.; Briz, V.; Chishti, A.; Bi, X.; Baudry, M. Distinct roles for μ-calpain and m-calpain in synaptic NMDAR-mediated neuroprotection and extrasynaptic NMDAR-mediated neurodegeneration. J. Neurosci., 2013, 33(48), 18880-18892.
[http://dx.doi.org/10.1523/JNEUROSCI.3293-13.2013] [PMID: 24285894]
[8]
Wu, H.Y.; Lynch, D.R. Calpain and synaptic function. Mol. Neurobiol., 2006, 33(3), 215-236.
[http://dx.doi.org/10.1385/MN:33:3:215] [PMID: 16954597]
[9]
Croall, D.E.; Ersfeld, K. The calpains: modular designs and functional diversity. Genome Biol., 2007, 8(6), 218.
[http://dx.doi.org/10.1186/gb-2007-8-6-218] [PMID: 17608959]
[10]
Ono, Y.; Sorimachi, H. Calpains: An elaborate proteolytic system. Biochim. Biophys. Acta, 2012, 1824(1), 224-236.
[http://dx.doi.org/10.1016/j.bbapap.2011.08.005] [PMID: 21864727]
[11]
Briz, V.; Hsu, Y.T.; Li, Y.; Lee, E.; Bi, X.; Baudry, M. Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis. J. Neurosci., 2013, 33(10), 4317-4328.
[http://dx.doi.org/10.1523/JNEUROSCI.4907-12.2013] [PMID: 23467348]
[12]
Panja, D.; Bramham, C.R. BDNF mechanisms in late LTP formation: A synthesis and breakdown. Neuropharmacology, 2014, 76(Pt C), 664-676.
[http://dx.doi.org/10.1016/j.neuropharm.2013.06.024] [PMID: 23831365]
[13]
Takei, N.; Inamura, N.; Kawamura, M.; Namba, H.; Hara, K.; Yonezawa, K.; Nawa, H. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J. Neurosci., 2004, 24(44), 9760-9769.
[http://dx.doi.org/10.1523/JNEUROSCI.1427-04.2004] [PMID: 15525761]
[14]
Briz, V.; Baudry, M. Estrogen regulates protein synthesis and actin polymerization in hippocampal neurons through different molecular mechanisms. Front. Endocrinol. (Lausanne), 2014, 5, 22.
[http://dx.doi.org/10.3389/fendo.2014.00022] [PMID: 24611062]
[15]
Wang, Y.; Liu, Y.; Lopez, D.; Lee, M.; Dayal, S.; Hurtado, A.; Bi, X.; Baudry, M. Protection against TBI-induced neuronal death with post-treatment with a selective calpain-2 inhibitor in mice. J. Neurotrauma, 2018, 35(1), 105-117.
[http://dx.doi.org/10.1089/neu.2017.5024] [PMID: 28594313]
[16]
Wang, Y.; Zhu, G.; Briz, V.; Hsu, Y.T.; Bi, X.; Baudry, M. A molecular brake controls the magnitude of long-term potentiation. Nat. Commun., 2014, 5, 3051.
[http://dx.doi.org/10.1038/ncomms4051] [PMID: 24394804]
[17]
Beltran, L.; Chaussade, C.; Vanhaesebroeck, B.; Cutillas, P.R. Calpain interacts with class IA phosphoinositide 3-kinases regulating their stability and signaling activity. Proc. Natl. Acad. Sci. USA, 2011, 108(39), 16217-16222.
[http://dx.doi.org/10.1073/pnas.1107692108] [PMID: 21930956]
[18]
Carlin, R.K.; Bartelt, D.C.; Siekevitz, P. Identification of fodrin as a major calmodulin-binding protein in postsynaptic density preparations. J. Cell Biol., 1983, 96(2), 443-448.
[http://dx.doi.org/10.1083/jcb.96.2.443] [PMID: 6833363]
[19]
Bennett, V. Spectrin-based membrane skeleton: a multipotential adaptor between plasma membrane and cytoplasm. Physiol. Rev., 1990, 70(4), 1029-1065.
[http://dx.doi.org/10.1152/physrev.1990.70.4.1029] [PMID: 2271059]
[20]
Ma, M. Role of calpains in the injury-induced dysfunction and degeneration of the mammalian axon. Neurobiol. Dis., 2013, 60, 61-79.
[http://dx.doi.org/10.1016/j.nbd.2013.08.010] [PMID: 23969238]
[21]
Banik, N.L.; Matzelle, D.; Terry, E.; Hogan, E.L. A new mechanism of methylprednisolone and other corticosteroids action demonstrated in vitro: inhibition of a proteinase (calpain) prevents myelin and cytoskeletal protein degradation. Brain Res., 1997, 748(1-2), 205-210.
[http://dx.doi.org/10.1016/S0006-8993(96)01302-9] [PMID: 9067463]
[22]
Fischer, I.; Romano-Clarke, G.; Grynspan, F. Calpain-mediated proteolysis of microtubule associated proteins MAP1B and MAP2 in developing brain. Neurochem. Res., 1991, 16(8), 891-898.
[http://dx.doi.org/10.1007/BF00965538] [PMID: 1787878]
[23]
Johnson, G.V.; Litersky, J.M.; Jope, R.S. Degradation of microtubule-associated protein 2 and brain spectrin by calpain: A comparative study. J. Neurochem., 1991, 56(5), 1630-1638.
[http://dx.doi.org/10.1111/j.1471-4159.1991.tb02061.x] [PMID: 2013758]
[24]
Potter, D.A.; Tirnauer, J.S.; Janssen, R.; Croall, D.E.; Hughes, C.N.; Fiacco, K.A.; Mier, J.W.; Maki, M.; Herman, I.M. Calpain regulates actin remodeling during cell spreading. J. Cell Biol., 1998, 141(3), 647-662.
[http://dx.doi.org/10.1083/jcb.141.3.647] [PMID: 9566966]
[25]
Perrin, B.J.; Amann, K.J.; Huttenlocher, A. Proteolysis of cortactin by calpain regulates membrane protrusion during cell migration. Mol. Biol. Cell, 2006, 17(1), 239-250.
[http://dx.doi.org/10.1091/mbc.e05-06-0488] [PMID: 16280362]
[26]
Chimura, T.; Launey, T.; Yoshida, N. Calpain-mediated degradation of drebrin by excitotoxicity In vitro and In vivo. PLoS One, 2015, 10(4), e0125119.
[http://dx.doi.org/10.1371/journal.pone.0125119] [PMID: 25905636]
[27]
Kulkarni, S.; Goll, D.E.; Fox, J.E. Calpain cleaves RhoA generating a dominant-negative form that inhibits integrin-induced actin filament assembly and cell spreading. J. Biol. Chem., 2002, 277(27), 24435-24441.
[http://dx.doi.org/10.1074/jbc.M203457200] [PMID: 11964413]
[28]
Briz, V.; Zhu, G.; Wang, Y.; Liu, Y.; Avetisyan, M.; Bi, X.; Baudry, M. Activity-dependent rapid local RhoA synthesis is required for hippocampal synaptic plasticity. J. Neurosci., 2015, 35(5), 2269-2282.
[http://dx.doi.org/10.1523/JNEUROSCI.2302-14.2015] [PMID: 25653381]
[29]
Du, X.; Saido, T.C.; Tsubuki, S.; Indig, F.E.; Williams, M.J.; Ginsberg, M.H. Calpain cleavage of the cytoplasmic domain of the integrin beta 3 subunit. J. Biol. Chem., 1995, 270(44), 26146-26151.
[http://dx.doi.org/10.1074/jbc.270.44.26146] [PMID: 7592818]
[30]
Pfaff, M.; Du, X.; Ginsberg, M.H. Calpain cleavage of integrin beta cytoplasmic domains. FEBS Lett., 1999, 460(1), 17-22.
[http://dx.doi.org/10.1016/S0014-5793(99)01250-8] [PMID: 10571053]
[31]
Kerstein, P.C.; Jacques-Fricke, B.T.; Rengifo, J.; Mogen, B.J.; Williams, J.C.; Gottlieb, P.A.; Sachs, F.; Gomez, T.M. Mechanosensitive TRPC1 channels promote calpain proteolysis of talin to regulate spinal axon outgrowth. J. Neurosci., 2013, 33(1), 273-285.
[http://dx.doi.org/10.1523/JNEUROSCI.2142-12.2013] [PMID: 23283340]
[32]
Dulong, S.; Goudenege, S.; Vuillier-Devillers, K.; Manenti, S.; Poussard, S.; Cottin, P. Myristoylated alanine-rich C kinase substrate (MARCKS) is involved in myoblast fusion through its regulation by protein kinase Calpha and calpain proteolytic cleavage. Biochem. J., 2004, 382(Pt 3), 1015-1023.
[http://dx.doi.org/10.1042/BJ20040347] [PMID: 15239673]
[33]
Klimaviciusa, L.; Safiulina, D.; Kaasik, A.; Klusa, V.; Zharkovsky, A. The effects of glutamate receptor antagonists on cerebellar granule cell survival and development. Neurotoxicology, 2008, 29(1), 101-108.
[http://dx.doi.org/10.1016/j.neuro.2007.09.006] [PMID: 17981335]
[34]
Coronado, V.G.; Xu, L.; Basavaraju, S.V. Surveillance for traumatic brain injury-related deaths: United States, 1997-2007. US Department of Health and Human Services, Centers for Disease Control and Prevention Atlanta, 2011
[35]
Vosler, P.S.; Brennan, C.S.; Chen, J. Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Mol. Neurobiol., 2008, 38(1), 78-100.
[http://dx.doi.org/10.1007/s12035-008-8036-x] [PMID: 18686046]
[36]
Jourdi, H.; Hamo, L.; Oka, T.; Seegan, A.; Baudry, M. BDNF mediates the neuroprotective effects of positive AMPA receptor modulators against MPP+-induced toxicity in cultured hippocampal and mesencephalic slices. Neuropharmacology, 2009, 56(5), 876-885.
[http://dx.doi.org/10.1016/j.neuropharm.2009.01.015] [PMID: 19371576]
[37]
Pannaccione, A.; Secondo, A.; Molinaro, P.; D’Avanzo, C.; Cantile, M.; Esposito, A.; Boscia, F.; Scorziello, A.; Sirabella, R.; Sokolow, S.; Herchuelz, A.; Di Renzo, G.; Annunziato, L. A new concept: Aβ1-42 generates a hyperfunctional proteolytic NCX3 fragment that delays caspase-12 activation and neuronal death. J. Neurosci., 2012, 32(31), 10609-10617.
[http://dx.doi.org/10.1523/JNEUROSCI.6429-11.2012] [PMID: 22855810]
[38]
Papouin, T.; Oliet, S.H. Organization, control and function of extrasynaptic NMDA receptors. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2014, 369(1654), 20130601.
[http://dx.doi.org/10.1098/rstb.2013.0601] [PMID: 25225095]
[39]
Chazot, P.L. The NMDA receptor NR2B subunit: A valid therapeutic target for multiple CNS pathologies. Curr. Med. Chem., 2004, 11(3), 389-396.
[http://dx.doi.org/10.2174/0929867043456061] [PMID: 14965239]
[40]
Hardingham, G.E.; Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci., 2010, 11(10), 682-696.
[http://dx.doi.org/10.1038/nrn2911] [PMID: 20842175]
[41]
Krapivinsky, G.; Krapivinsky, L.; Manasian, Y.; Ivanov, A.; Tyzio, R.; Pellegrino, C.; Ben-Ari, Y.; Clapham, D.E.; Medina, I. The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron, 2003, 40(4), 775-784.
[http://dx.doi.org/10.1016/S0896-6273(03)00645-7] [PMID: 14622581]
[42]
Zadran, S.; Jourdi, H.; Rostamiani, K.; Qin, Q.; Bi, X.; Baudry, M. Brain-derived neurotrophic factor and epidermal growth factor activate neuronal m-calpain via mitogen-activated protein kinase-dependent phosphorylation. J. Neurosci., 2010, 30(3), 1086-1095.
[http://dx.doi.org/10.1523/JNEUROSCI.5120-09.2010] [PMID: 20089917]
[43]
Xu, J.; Kurup, P.; Zhang, Y.; Goebel-Goody, S.M.; Wu, P.H.; Hawasli, A.H.; Baum, M.L.; Bibb, J.A.; Lombroso, P.J. Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J. Neurosci., 2009, 29(29), 9330-9343.
[http://dx.doi.org/10.1523/JNEUROSCI.2212-09.2009] [PMID: 19625523]
[44]
Gladding, C.M.; Sepers, M.D.; Xu, J.; Zhang, L.Y.J.; Milnerwood, A.J.; Lombroso, P.J.; Raymond, L.A. Calpain and STriatal-Enriched protein tyrosine phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington’s disease mouse model. Hum. Mol. Genet., 2012, 21(17), 3739-3752.
[http://dx.doi.org/10.1093/hmg/dds154] [PMID: 22523092]
[45]
Wang, Y.; Lopez, D.; Davey, P.G.; Cameron, D.J.; Nguyen, K.; Tran, J.; Marquez, E.; Liu, Y.; Bi, X.; Baudry, M. Calpain-1 and calpain-2 play opposite roles in retinal ganglion cell degeneration induced by retinal ischemia/reperfusion injury. Neurobiol. Dis., 2016, 93, 121-128.
[http://dx.doi.org/10.1016/j.nbd.2016.05.007] [PMID: 27185592]
[46]
Hanna, R.A.; Campbell, R.L.; Davies, P.L. Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin. Nature, 2008, 456(7220), 409-412.
[http://dx.doi.org/10.1038/nature07451] [PMID: 19020623]
[47]
Wang, Y.; Bi, X.; Baudry, M. Calpain-2 as a therapeutic target for acute neuronal injury. Expert Opin. Ther. Targets, 2018, 22(1), 19-29.
[http://dx.doi.org/10.1080/14728222.2018.1409723] [PMID: 29168923]
[48]
Liu, Y.; Wang, Y.; Zhu, G.; Sun, J.; Bi, X.; Baudry, M. A calpain-2 selective inhibitor enhances learning & memory by prolonging ERK activation. Neuropharmacology, 2016, 105, 471-477.
[http://dx.doi.org/10.1016/j.neuropharm.2016.02.022] [PMID: 26907807]
[49]
Binder, S.; Corrigan, J.D.; Langlois, J.A. The public health approach to traumatic brain injury: an overview of CDC’s research and programs. J. Head Trauma Rehabil., 2005, 20(3), 189-195.
[http://dx.doi.org/10.1097/00001199-200505000-00002] [PMID: 15908819]
[50]
Dewan, M.C.; Rattani, A.; Gupta, S.; Baticulon, R.E.; Hung, Y.C.; Punchak, M. Agrawal.A., Adeley, A.O., Shime, M.G., Rubiano, A.M., Rosenfeld, J.V. and Park, K.B. Estimating the global incidence of traumatic brain injury. J. Neurosurg., 2018, 1-18.
[http://dx.doi.org/10.3171/2017.10.JNS17352]
[51]
Mustafa, A.G.; Alshboul, O.A. Pathophysiology of traumatic brain injury. Neurosciences (Riyadh), 2013, 18(3), 222-234.
[PMID: 23887212]
[52]
Bauer, D.; Tung, M.L.; Tsao, J.W. Mechanisms of traumatic brain injury. Semin. Neurol., 2015, 35(1), e14-e22.
[http://dx.doi.org/10.1055/s-0035-1549095] [PMID: 25816125]
[53]
Quillinan, N.; Herson, P.S.; Traystman, R.J. Neuropathophysiology of brain injury. Anesthesiol. Clin., 2016, 34(3), 453-464.
[http://dx.doi.org/10.1016/j.anclin.2016.04.011] [PMID: 27521191]
[54]
Siman, R.; Giovannone, N.; Hanten, G.; Wilde, E.A.; McCauley, S.R.; Hunter, J.V.; Li, X.; Levin, H.S.; Smith, D.H. Evidence that the blood biomarker SNTF predicts brain imaging changes and persistent cognitive dysfunction in mild TBI patients. Front. Neurol., 2013, 4, 190.
[http://dx.doi.org/10.3389/fneur.2013.00190] [PMID: 24302918]
[55]
Vile, A.R.; Atkinson, L. Chronic traumatic encephalopathy: The cellular sequela to repetitive brain injury. J. Clin. Neurosci., 2017, 41, 24-29.
[http://dx.doi.org/10.1016/j.jocn.2017.03.035] [PMID: 28347679]
[56]
Chatterjee, P.; Botello-Smith, W.M.; Zhang, H.; Qian, L.; Alsamarah, A.; Kent, D.; Lacroix, J.J.; Baudry, M.; Luo, Y. Can relative binding free energy predict selectivity of reversible covalent inhibitors? J. Am. Chem. Soc., 2017, 139(49), 17945-17952.
[http://dx.doi.org/10.1021/jacs.7b08938] [PMID: 29124934]


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VOLUME: 17
ISSUE: 9
Year: 2019
Page: [823 - 829]
Pages: 7
DOI: 10.2174/1570159X17666190228112451

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