title: Bax regulates neuronal Ca2+ homeostasis.
abstract: Excessive Ca(2+) entry during glutamate receptor overactivation ("excitotoxicity") induces acute or delayed neuronal death. We report here that deficiency in bax exerted broad neuroprotection against excitotoxic injury and oxygen/glucose deprivation in mouse neocortical neuron cultures and reduced infarct size, necrotic injury, and cerebral edema formation after middle cerebral artery occlusion in mice. Neuronal Ca(2+) and mitochondrial membrane potential (Δψm) analysis during excitotoxic injury revealed that bax-deficient neurons showed significantly reduced Ca(2+) transients during the NMDA excitation period and did not exhibit the deregulation of Δψm that was observed in their wild-type (WT) counterparts. Reintroduction of bax or a bax mutant incapable of proapoptotic oligomerization equally restored neuronal Ca(2+) dynamics during NMDA excitation, suggesting that Bax controlled Ca(2+) signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca(2+) levels using FRET-based sensors indicated that the effects of bax deficiency on Ca(2+) handling were not due to enhanced cellular bioenergetics or increased Ca(2+) uptake into mitochondria. We also observed that mitochondria isolated from WT or bax-deficient cells similarly underwent Ca(2+)-induced permeability transition. However, when Ca(2+) uptake into the sarco/endoplasmic reticulum was blocked with the Ca(2+)-ATPase inhibitor thapsigargin, bax-deficient neurons showed strongly elevated cytosolic Ca(2+) levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca(2+) handling is critical for cell death signaling during periods of neuronal overexcitation.
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and.
authors: Beatrice
authors: B
authors: D'Orsi
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and.
authors: Seán M
authors: SM
authors: Kilbride
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and.
authors: Gang
authors: G
authors: Chen
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and.
authors: Sergio
authors: S
authors: Perez Alvarez
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and.
authors: Helena P
authors: HP
authors: Bonner
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and.
authors: Shona
authors: S
authors: Pfeiffer
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and Institute for Stroke and Dementia Research, DZNE, Groβhadern, D-81377 Munich, Germany.
authors: Nikolaus
authors: N
authors: Plesnila
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and.
authors: Tobias
authors: T
authors: Engel
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and.
authors: David C
authors: DC
authors: Henshall
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and.
authors: Heiko
authors: H
authors: Düssmann
authors: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders and 3U-COEN, Royal College of Surgeons in Ireland, Dublin 2, Ireland; and prehn@rcsi.ie.
authors: Jochen H M
authors: JH
authors: Prehn
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D016202:N-Methylaspartate / Q000494:pharmacology; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494827:Bax protein, mouse; D018690:Excitatory Amino Acid Agonists; D051028:bcl-2-Associated X Protein; D016202:N-Methylaspartate; D005947:Glucose; D002118:Calcium
keywords: Bcl-2 family protein; NMDA; cerebral ischemia; endoplasmic reticulum; excitotoxicity; mitochondria
references: J Cell Biol. 1997 Oct 6;139(1):205-17
references: 9314540
references: Oncogene. 2002 Jun 6;21(25):4009-19
references: 12037683
references: Nat Rev Neurosci. 2010 Oct;11(10):682-96
references: 20842175
references: J Cell Biol. 2004 Jul 19;166(2):193-203
references: 15263017
references: J Biol Chem. 2001 Nov 23;276(47):44117-28
references: 11546793
references: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3668-72
references: 9108035
references: Nature. 2005 Mar 31;434(7033):652-8
references: 15800626
references: J Biol Chem. 1999 May 14;274(20):14157-62
references: 10318833
references: J Cell Biol. 2002 Dec 23;159(6):931-8
references: 12499352
references: Genes Dev. 2007 Aug 1;21(15):1937-48
references: 17671092
references: Cell Death Dis. 2013 May 16;4:e632
references: 23681227
references: Biochim Biophys Acta. 2004 Jan 20;1676(2):127-37
references: 14746907
references: Dev Neurosci. 2014;36(1):64-72
references: 24525800
references: Mol Cell Biol. 2001 Jan;21(2):678-89
references: 11134353
references: Ann N Y Acad Sci. 2008 Dec;1147:233-41
references: 19076445
references: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14397-402
references: 19706527
references: J Neurochem. 2005 Feb;92(3):678-91
references: 15659237
references: Neuron. 1996 Sep;17(3):401-11
references: 8816704
references: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7162-6
references: 7638161
references: Apoptosis. 2006 Jun;11(6):967-81
references: 16763784
references: J Biol Chem. 2000 Jun 2;275(22):17064-71
references: 10828077
references: Science. 1997 Jul 18;277(5324):370-2
references: 9219694
references: Bioorg Med Chem Lett. 2000 Jul 17;10(14):1515-8
references: 10915039
references: J Physiol. 2004 Feb 1;554(Pt 3):815-28
references: 14608004
references: J Vis Exp. 2009 Jan 19;(23):null
references: 19229178
references: Oncogene. 2013 May 30;32(22):2703-11
references: 22869150
references: Development. 1997 Mar;124(6):1239-49
references: 9102310
references: Aging Cell. 2007 Jun;6(3):337-50
references: 17328689
references: Cell Death Differ. 2005 Feb;12(2):162-76
references: 15592434
references: Exp Neurol. 2009 Aug;218(2):171-82
references: 19236863
references: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5723-8
references: 10823933
references: J Immunol. 2001 Mar 1;166(5):3130-42
references: 11207265
references: J Cell Biol. 1997 Sep 22;138(6):1219-28
references: 9298978
references: J Neurochem. 1996 Dec;67(6):2282-91
references: 8931459
references: J Neurosci. 2007 Nov 21;27(47):12989-99
references: 18032672
references: Mol Cell. 2008 Aug 22;31(4):570-85
references: 18722181
references: J Cell Biol. 2002 Aug 5;158(3):507-17
references: 12147675
references: Science. 2002 Jul 12;297(5579):259-63
references: 12114629
references: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):105-10
references: 15613488
references: J Biol Chem. 2005 Jun 24;280(25):23829-36
references: 15809295
references: Mol Cell. 2010 Feb 12;37(3):299-310
references: 20159550
references: J Neurosci. 2000 Aug 1;20(15):5715-23
references: 10908611
references: Genes Dev. 2010 Dec 1;24(23):2592-602
references: 21123646
references: Oncogene. 2004 Feb 12;23(6):1248-55
references: 14647416
references: J Biol Chem. 2004 Apr 30;279(18):19133-40
references: 14966123
references: Elife. 2013 Aug 27;2:e00772
references: 23991283
references: J Neurosci. 1987 Feb;7(2):369-79
references: 2880938
references: Am J Pathol. 2007 Oct;171(4):1258-68
references: 17702891
references: Cell Death Differ. 2008 Dec;15(12):1857-64
references: 18806756
references: Mol Biol Rep. 2002;29(1-2):93-6
references: 12243190
references: J Biol Chem. 2005 Mar 11;280(10):9065-73
references: 15590665
references: Oncogene. 1996 May 16;12(10):2051-5
references: 8668330
references: Zhonghua Er Bi Yan Hou Ke Za Zhi. 2004 Mar;39(3):157-61
references: 15283295
references: J Neurosci. 2007 Aug 29;27(35):9278-93
references: 17728442
references: Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2004 Aug;12(4):436-40
references: 15363126
references: J Cereb Blood Flow Metab. 2000 Sep;20(9):1294-300
references: 10994850
references: J Biol Chem. 1985 Mar 25;260(6):3440-50
references: 3838314
references: Int J Cancer. 2004 Mar;109(1):49-57
references: 14735467
references: Pflugers Arch. 2010 Jul;460(2):525-42
references: 20229265
references: J Biol Chem. 2003 Jul 25;278(30):27382-9
references: 12750371
references: Chem Biol. 2006 May;13(5):521-30
references: 16720273
references: J Neurosci. 1999 Sep 1;19(17):7476-85
references: 10460254
references: Cell Death Differ. 2010 Feb;17(2):278-90
references: 19745831
references: Nat Rev Neurosci. 2009 Jul;10(7):481-94
references: 19543220
references: FASEB J. 2002 Apr;16(6):607-9
references: 11919169
references: Blood. 2005 Mar 15;105(6):2504-9
references: 15454489
references: Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59
references: 18097445
references: Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6569-73
references: 8022822
references: Neuroscience. 2010 Jun 30;168(2):443-50
references: 20362645
references: J Neurosci. 2007 Aug 1;27(31):8238-49
references: 17670970
references: Cell Death Differ. 2006 Aug;13(8):1409-18
references: 16729032
references: Nat Rev Mol Cell Biol. 2012 Sep;13(9):566-78
references: 22850819
references: J Neurosci. 1999 Sep 15;19(18):7860-9
references: 10479688
references: Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2004 Dec;12(6):752-6
references: 15631654
references: J Cell Biol. 2003 Aug 18;162(4):587-97
references: 12913114
references: FEBS Lett. 1998 Nov 20;439(3):373-6
references: 9845356
references: J Neurosci. 2004 Dec 1;24(48):10963-73
references: 15574746
references: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15318-23
references: 11742085
references: Nature. 1997 Aug 28;388(6645):882-7
references: 9278050
references: Breast. 2004 Jun;13(3):227-31
references: 15177426
references: J Neurosci. 2006 Mar 15;26(11):2956-63
references: 16540573
references: J Neurosci. 2011 Feb 23;31(8):2996-3006
references: 21414921
references: Mol Pharmacol. 2001 Nov;60(5):1008-19
references: 11641429
references: Neuron. 1995 Oct;15(4):961-73
references: 7576644
references: J Cell Biol. 1998 Oct 5;143(1):207-15
references: 9763432
references: Nat Cell Biol. 2005 Oct;7(10):1021-8
references: 16179951
references: Nat Protoc. 2007;2(2):287-95
references: 17406588
references: Cell Calcium. 1985 Apr;6(1-2):145-57
references: 3874696
references: J Neurosci. 1993 Aug;13(8):3510-24
references: 8101871
references: Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15540-5
references: 17030815
references: J Neurosci. 2007 Mar 14;27(11):2846-57
references: 17360906
references: J Cereb Blood Flow Metab. 1998 May;18(5):570-9
references: 9591849
references: Science. 2003 Apr 4;300(5616):135-9
references: 12624178
references: J Neurosci. 1998 Feb 15;18(4):1363-73
references: 9454845
references: J Neurosci. 2012 Feb 1;32(5):1847-58
references: 22302823
references: Cell Death Differ. 1999 Sep;6(9):825-32
references: 10510464
references: Cancer Lett. 2004 Mar 8;205(1):81-8
references: 15036664
references: Br J Cancer. 1997;75(4):545-7
references: 9052408
references: J Cell Biol. 2011 Oct 17;195(2):263-76
references: 21987637
references: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14681-6
references: 9843949
references: Nature. 2006 Oct 12;443(7112):658-62
references: 17035996
references: J Cell Biol. 2000 Mar 6;148(5):857-62
references: 10704437
references: Acta Pharmacol Sin. 2004 Aug;25(8):1090-5
references: 15301745
references: J Biol Chem. 2001 May 11;276(19):16240-7
references: 11278671
references: FASEB J. 2012 Apr;26(4):1616-28
references: 22198387
references: Nat Neurosci. 1998 Sep;1(5):366-73
references: 10196525
references: J Biol Chem. 2001 Nov 16;276(46):43435-45
references: 11546795
references: Mol Med. 2001 Sep;7(9):644-55
references: 11778654
references: Transplant Proc. 2004 Dec;36(10):2924-6
references: 15686661
references: Neuron. 2012 May 10;74(3):543-56
references: 22578505
references: Cell Death Differ. 1996 Jul;3(3):331-7
references: 17180102
references: J Exp Bot. 2004 Dec;55(408):2617-23
references: 15475374
references: Eur J Pharmacol. 2004 Oct 19;502(3):169-83
references: 15476743
references: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15651-6
references: 19720993
references: Nat Rev Mol Cell Biol. 2003 Jul;4(7):579-86
references: 12838340
references: Nat Cell Biol. 2011 Sep 18;13(10):1224-33
references: 21926988
references: PLoS Biol. 2007 Jul;5(7):e189
references: 17622195
references: Neuron. 1998 Oct;21(4):695-705
references: 9808457
references: World J Gastroenterol. 2004 Sep 15;10(18):2706-10
references: 15309723
references: J Cereb Blood Flow Metab. 2005 Aug;25(8):978-89
references: 15815587