Abstract
Activation of glutamate receptors and followed increase of intracellular calcium concentration is a key pathological mechanism involved in secondary neuronal injury after traumatic brain injury (TBI). Stromal interaction molecule (STIM) proteins are considered to be important players in regulating neuronal Ca2+ homeostasis under normal aging and pathological conditions. Here, we investigated the role of STIM1 in regulating metabotropic glutamate receptor 1 (mGluR1)-related Ca2+ signaling and neuronal survival by using an in vitro traumatic neuronal injury (TNI) model. The expression of STIM1 was significantly increased at both mRNA and protein levels after TNI. Down-regulation of STIM1 by specific small interfere RNA significantly preserved neuronal viability, decreased lactate dehydrogenase release, and inhibited apoptotic cell death after traumatic injury. Moreover, knockdown of STIM1 significantly alleviated the mGluR1-related increase of cytoplasmic Ca2+ levels after TNI. By analyzing Ca2+ imaging in Ca2+-free conditions, we demonstrated that the mGluR1-dependent inositol trisphosphate receptor and/or ryanodine receptor-mediated Ca2+ release from the endoplasmic reticulum after TNI is strongly attenuated in the absence of STIM1. Together, our results demonstrate that in the mammalian nervous system, STIM1 is a key regulator of mGluR1-dependent Ca2+ signaling and knockdown of STIM1 might be an effective intervention target in TBI.
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Abramov AY, Duchen MR (2008) Mechanisms underlying the loss of mitochondrial membrane potential in glutamate excitotoxicity. Biochim Biophys Acta 1777(7–8):953–964. doi:10.1016/j.bbabio.2008.04.017
Algattas H, Huang JH (2014) Traumatic brain injury pathophysiology and treatments: early, intermediate, and late phases post-injury. Int J Mol Sci 15(1):309–341. doi:10.3390/ijms15010309
Arundine M, Tymianski M (2004) Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci 61(6):657–668. doi:10.1007/s00018-003-3319-x
Baba Y, Kurosaki T (2009) Physiological function and molecular basis of STIM1-mediated calcium entry in immune cells. Immunol Rev 231(1):174–188. doi:10.1111/j.1600-065X.2009.00813.x
Batchelor AM, Madge DJ, Garthwaite J (1994) Synaptic activation of metabotropic glutamate receptors in the parallel fibre-Purkinje cell pathway in rat cerebellar slices. Neuroscience 63(4):911–915
Belousov AB (2012) Novel model for the mechanisms of glutamate-dependent excitotoxicity: role of neuronal gap junctions. Brain Res 1487:123–130. doi:10.1016/j.brainres.2012.05.063
Chen T, Liu W, Chao X, Zhang L, Qu Y, Huo J, Fei Z (2011) Salvianolic acid B attenuates brain damage and inflammation after traumatic brain injury in mice. Brain Res Bull 84(2):163–168. doi:10.1016/j.brainresbull.2010.11.015
Chen T, Cao L, Dong W, Luo P, Liu W, Qu Y, Fei Z (2012a) Protective effects of mGluR5 positive modulators against traumatic neuronal injury through PKC-dependent activation of MEK/ERK pathway. Neurochem Res 37(5):983–990. doi:10.1007/s11064-011-0691-z
Chen T, Fei F, Jiang XF, Zhang L, Qu Y, Huo K, Fei Z (2012b) Down-regulation of Homer1b/c attenuates glutamate-mediated excitotoxicity through endoplasmic reticulum and mitochondria pathways in rat cortical neurons. Free Radic Biol Med 52(1):208–217. doi:10.1016/j.freeradbiomed.2011.10.451
Chen T, Zhang L, Qu Y, Huo K, Jiang X, Fei Z (2012c) The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway. Int J Mol Med 29(4):630–636. doi:10.3892/ijmm.2011.870
Chen T, Yang YF, Luo P, Liu W, Dai SH, Zheng XR, Fei Z, Jiang XF (2013a) Homer1 knockdown protects dopamine neurons through regulating calcium homeostasis in an in vitro model of Parkinson’s disease. Cell Signal 25(12):2863–2870. doi:10.1016/j.cellsig.2013.09.004
Chen T, Zhu J, Zhang C, Huo K, Fei Z, Jiang XF (2013b) Protective effects of SKF-96365, a non-specific inhibitor of SOCE, against MPP + -induced cytotoxicity in PC12 cells: potential role of Homer1. PLoS One 8(1):e55601. doi:10.1371/journal.pone.0055601
Cheng G, Kong RH, Zhang LM, Zhang JN (2012) Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br J Pharmacol 167(4):699–719. doi:10.1111/j.1476-5381.2012.02025.x
Cucchiaroni ML, Viscomi MT, Bernardi G, Molinari M, Guatteo E, Mercuri NB (2010) Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-l-alanine on substantia nigra pars compacta DAergic neurons. J Neurosci 30(15):5176–5188. doi:10.1523/JNEUROSCI.5351-09.2010
Dziadek MA, Johnstone LS (2007) Biochemical properties and cellular localisation of STIM proteins. Cell Calcium 42(2):123–132. doi:10.1016/j.ceca.2007.02.006
Faden AI, O’Leary DM, Fan L, Bao W, Mullins PG, Movsesyan VA (2001) Selective blockade of the mGluR1 receptor reduces traumatic neuronal injury in vitro and improvesoOutcome after brain trauma. Exp Neurol 167(2):435–444. doi:10.1006/exnr.2000.7577
Fahrner M, Muik M, Derler I, Schindl R, Fritsch R, Frischauf I, Romanin C (2009) Mechanistic view on domains mediating STIM1-Orai coupling. Immunol Rev 231(1):99–112. doi:10.1111/j.1600-065X.2009.00815.x
Fei Z, Zhang X, Jiang XF, Huang WD, Bai HM (2005) Altered expression patterns of metabotropic glutamate receptors in diffuse brain injury. Neurosci Lett 380(3):280–283. doi:10.1016/j.neulet.2005.01.063
Fei Z, Zhang X, Bai HM, Jiang XF, Wang XL (2006) Metabotropic glutamate receptor antagonists and agonists: potential neuroprotectors in diffuse brain injury. J Clin Neurosci 13(10):1023–1027. doi:10.1016/j.jocn.2005.11.042
Feyen BF, Sener S, Jorens PG, Menovsky T, Maas AI (2012) Neuromonitoring in traumatic brain injury. Minerva Anestesiol 78(8):949–958
Finch EA, Augustine GJ (1998) Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites. Nature 396(6713):753–756. doi:10.1038/25541
Ghajar J (2000) Traumatic brain injury. Lancet 356(9233):923–929. doi:10.1016/S0140-6736(00)02689-1
Gong QZ, Delahunty TM, Hamm RJ, Lyeth BG (1995) Metabotropic glutamate antagonist, MCPG, treatment of traumatic brain injury in rats. Brain Res 700(1–2):299–302
Goudet C, Magnaghi V, Landry M, Nagy F, Gereau RWt, Pin JP (2009) Metabotropic receptors for glutamate and GABA in pain. Brain Res Rev 60(1):43–56. doi:10.1016/j.brainresrev.2008.12.007
Gruszczynska-Biegala J, Pomorski P, Wisniewska MB, Kuznicki J (2011) Differential roles for STIM1 and STIM2 in store-operated calcium entry in rat neurons. PLoS One 6(4):e19285. doi:10.1371/journal.pone.0019285
Harraz OF, Altier C (2014) STIM1-mediated bidirectional regulation of Ca(2 +) entry through voltage-gated calcium channels (VGCC) and calcium-release activated channels (CRAC). Front Cell Neurosci 8:43. doi:10.3389/fncel.2014.00043
Hartmann J, Karl RM, Alexander RP, Adelsberger H, Brill MS, Ruhlmann C, Ansel A, Sakimura K, Baba Y, Kurosaki T, Misgeld T, Konnerth A (2014) STIM1 controls neuronal Ca(2)(+) signaling, mGluR1-dependent synaptic transmission, and cerebellar motor behavior. Neuron 82(3):635–644. doi:10.1016/j.neuron.2014.03.027
Hayashi MK, Tang C, Verpelli C, Narayanan R, Stearns MH, Xu RM, Li H, Sala C, Hayashi Y (2009) The postsynaptic density proteins Homer and Shank form a polymeric network structure. Cell 137(1):159–171. doi:10.1016/j.cell.2009.01.050
Huang WD, Fei Z, Zhang X (2005) Traumatic injury induced homer-1a gene expression in cultured cortical neurons of rat. Neurosci Lett 389(1):46–50. doi:10.1016/j.neulet.2005.07.014
Klejman ME, Gruszczynska-Biegala J, Skibinska-Kijek A, Wisniewska MB, Misztal K, Blazejczyk M, Bojarski L, Kuznicki J (2009) Expression of STIM1 in brain and puncta-like co-localization of STIM1 and ORAI1 upon depletion of Ca(2 +) store in neurons. Neurochem Int 54(1):49–55. doi:10.1016/j.neuint.2008.10.005
Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 460(2):525–542. doi:10.1007/s00424-010-0809-1
Li Y, Song J, Liu X, Zhang M, An J, Sun P, Li D, Jin T, Wang J (2013) High expression of STIM1 in the early stages of diffuse axonal injury. Brain Res 1495:95–102. doi:10.1016/j.brainres.2012.12.005
Li B, Xiao L, Wang ZY, Zheng PS (2014) Knockdown of STIM1 inhibits 6-hydroxydopamine-induced oxidative stress through attenuating calcium-dependent ER stress and mitochondrial dysfunction in undifferentiated PC12 cells. Free Radical Res 48(7):758–768. doi:10.3109/10715762.2014.905687
Ng AN, Krogh M, Toresson H (2011) Dendritic EGFP-STIM1 activation after type I metabotropic glutamate and muscarinic acetylcholine receptor stimulation in hippocampal neuron. J Neurosci Res 89(8):1235–1244. doi:10.1002/jnr.22648
O’Shea RD (2002) Roles and regulation of glutamate transporters in the central nervous system. Clin Exp Pharmacol Physiol 29(11):1018–1023
Parekh AB, Putney JW Jr (2005) Store-operated calcium channels. Physiol Rev 85(2):757–810. doi:10.1152/physrev.00057.2003
Potier M, Gonzalez JC, Motiani RK, Abdullaev IF, Bisaillon JM, Singer HA, Trebak M (2009) Evidence for STIM1- and Orai1-dependent store-operated calcium influx through ICRAC in vascular smooth muscle cells: role in proliferation and migration. FASEB J 23(8):2425–2437. doi:10.1096/fj.09-131128
Raghupathi R (2004) Cell death mechanisms following traumatic brain injury. Brain Pathol 14(2):215–222
Schindl R, Muik M, Fahrner M, Derler I, Fritsch R, Bergsmann J, Romanin C (2009) Recent progress on STIM1 domains controlling Orai activation. Cell Calcium 46(4):227–232. doi:10.1016/j.ceca.2009.08.003
Smith JS, Fulop ZL, Levinsohn SA, Darrell RS, Stein DG (2000) Effects of the novel NMDA receptor antagonist gacyclidine on recovery from medial frontal cortex contusion injury in rats. Neural plasticity 7(1–2):73–91. doi:10.1155/NP.2000.73
Stoica BA, Faden AI (2010) Cell death mechanisms and modulation in traumatic brain injury. Neurotherapeutics 7(1):3–12. doi:10.1016/j.nurt.2009.10.023
Stone TW, Addae JI (2002) The pharmacological manipulation of glutamate receptors and neuroprotection. Eur J Pharmacol 447(2–3):285–296
Urra H, Dufey E, Lisbona F, Rojas-Rivera D, Hetz C (2013) When ER stress reaches a dead end. Biochimica Et Biophysica Acta 1833(12):3507–3517. doi:10.1016/j.bbamcr.2013.07.024
Worley PF, Zeng W, Huang GN, Yuan JP, Kim JY, Lee MG, Muallem S (2007) TRPC channels as STIM1-regulated store-operated channels. Cell Calcium 42(2):205–211. doi:10.1016/j.ceca.2007.03.004
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Peng-Fei Hou and Zhan-Hui Liu have contributed equally to this work.
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Hou, PF., Liu, ZH., Li, N. et al. Knockdown of STIM1 Improves Neuronal Survival After Traumatic Neuronal Injury Through Regulating mGluR1-Dependent Ca2+ Signaling in Mouse Cortical Neurons. Cell Mol Neurobiol 35, 283–292 (2015). https://doi.org/10.1007/s10571-014-0123-0
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DOI: https://doi.org/10.1007/s10571-014-0123-0