QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (388) Citing Articles via Google Scholar Google Scholar Articles by White, R. J. Articles by Reynolds, I. J. Search for Related Content PubMed PubMed Citation Articles by White, R. J. Articles by Reynolds, I. J.

 Previous Article  |  Next Article 

Volume 16, Number 18, Issue of September 15, 1996 pp. 5688-5697
Copyright ©1996 Society for Neuroscience

Mitochondrial Depolarization in Glutamate-Stimulated Neurons: An Early Signal Specific to Excitotoxin Exposure

Received April 26, 1996; revised June 26, 1996; accepted June 28, 1996.

R. James White and Ian J. Reynolds

Center for Neuroscience and Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

A brief exposure to high concentrations of glutamate kills cultured forebrain neurons by an excitotoxic process that is dependent on Ca²⁺ influx through the NMDA receptor. In this study, we have measured striking changes in mitochondrial function during and immediately after intense glutamate receptor activation. Using indo-1 microfluorometry and a specific inhibitor of the mitochondrial Na⁺/Ca²⁺ exchanger, CGP-37157, we have demonstrated that mitochondria accumulate large quantities of Ca²⁺ during a toxic glutamate stimulus and further that Ca²⁺ efflux from mitochondria contributes to the prolonged [Ca²⁺]_i elevation after glutamate removal. We then used JC-1 (5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazolocarbocyanine iodide), a ratiometric indicator of mitochondrial membrane potential (), to show that Ca²⁺ accumulation within the organelle dissipates . The abrupt loss of after glutamate stimulation did not occur in the presence of MK801 or in the absence of extracellular Ca²⁺. The mitochondrial depolarization was also cyclosporin A-sensitive, indicating a probable role for the permeability transition pore. Hence mitochondrial Ca²⁺ accumulation and the subsequent permeability transition may be a critical early event specific to the NMDA receptor-mediated excitotoxic cascade.

Key words: intracellular calcium; permeability transition pore; NMDA; excitotoxicity; forebrain neurons; CGP-37157

This article has been cited by other articles:

				Z. Guo, H. Jiang, X. Xu, W. Duan, and M. P. Mattson Leptin-mediated Cell Survival Signaling in Hippocampal Neurons Mediated by JAK STAT3 and Mitochondrial Stabilization J. Biol. Chem., January 18, 2008; 283(3): 1754 - 1763. [Abstract] [Full Text] [PDF]

				J. Shao, C. C. White, M. J. Dabrowski, T. J. Kavanagh, M. L. Eckert, and E. P. Gallagher The Role of Mitochondrial and Oxidative Injury in BDE 47 Toxicity to Human Fetal Liver Hematopoietic Stem Cells Toxicol. Sci., January 1, 2008; 101(1): 81 - 90. [Abstract] [Full Text] [PDF]

				C. W. Lee and H. B. Peng The Function of Mitochondria in Presynaptic Development at the Neuromuscular Junction Mol. Biol. Cell, January 1, 2008; 19(1): 150 - 158. [Abstract] [Full Text] [PDF]

				Y. Duan, R. A. Gross, and S.-S. Sheu Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity J. Physiol., December 15, 2007; 585(3): 741 - 758. [Abstract] [Full Text] [PDF]

				G. Giordano, C. C. White, I. Mohar, T. J. Kavanagh, and L. G. Costa Glutathione Levels Modulate Domoic Acid Induced Apoptosis in Mouse Cerebellar Granule Cells Toxicol. Sci., December 1, 2007; 100(2): 433 - 444. [Abstract] [Full Text] [PDF]

				M. W. Ward, H. J. Huber, P. Weisova, H. Dussmann, D. G. Nicholls, and J. H. M. Prehn Mitochondrial and Plasma Membrane Potential of Cultured Cerebellar Neurons during Glutamate-Induced Necrosis, Apoptosis, and Tolerance J. Neurosci., August 1, 2007; 27(31): 8238 - 8249. [Abstract] [Full Text] [PDF]

				K. K. Naga, P. G. Sullivan, and J. W. Geddes High Cyclophilin D Content of Synaptic Mitochondria Results in Increased Vulnerability to Permeability Transition J. Neurosci., July 11, 2007; 27(28): 7469 - 7475. [Abstract] [Full Text] [PDF]

				N. Shalbuyeva, T. Brustovetsky, and N. Brustovetsky Lithium Desensitizes Brain Mitochondria to Calcium, Antagonizes Permeability Transition, and Diminishes Cytochrome c Release J. Biol. Chem., June 22, 2007; 282(25): 18057 - 18068. [Abstract] [Full Text] [PDF]

				A. R. Genazzani, N. Pluchino, S. Luisi, and M. Luisi Estrogen, cognition and female ageing Hum. Reprod. Update, March 1, 2007; 13(2): 175 - 187. [Abstract] [Full Text] [PDF]

				D. B. Kintner, J. Luo, J. Gerdts, A. J. Ballard, G. E. Shull, and D. Sun Role of Na+-K+-Cl- cotransport and Na+/Ca2+ exchange in mitochondrial dysfunction in astrocytes following in vitro ischemia Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1113 - C1122. [Abstract] [Full Text] [PDF]

				N. Shalbuyeva, T. Brustovetsky, A. Bolshakov, and N. Brustovetsky Calcium-dependent Spontaneously Reversible Remodeling of Brain Mitochondria J. Biol. Chem., December 8, 2006; 281(49): 37547 - 37558. [Abstract] [Full Text] [PDF]

				D. Sareen, P. R. van Ginkel, J. C. Takach, A. Mohiuddin, S. R. Darjatmoko, D. M. Albert, and A. S. Polans Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells. Invest. Ophthalmol. Vis. Sci., September 1, 2006; 47(9): 3708 - 3716. [Abstract] [Full Text] [PDF]

				I. Kaddour-Djebbar, V. Lakshmikanthan, R. B. Shirley, Y. Ma, R. W. Lewis, and M. V. Kumar Therapeutic advantage of combining calcium channel blockers and TRAIL in prostate cancer. Mol. Cancer Ther., August 1, 2006; 5(8): 1958 - 1966. [Abstract] [Full Text] [PDF]

				C. Jacquard, Y. Trioulier, F. Cosker, C. Escartin, N. Bizat, P. Hantraye, J. M. Cancela, G. Bonvento, and E. Brouillet Brain mitochondrial defects amplify intracellular [Ca2+] rise and neurodegeneration but not Ca2+ entry during NMDA receptor activation FASEB J, May 1, 2006; 20(7): 1021 - 1023. [Abstract] [Full Text] [PDF]

				F. X. Soriano, S. Papadia, F. Hofmann, N. R. Hardingham, H. Bading, and G. E. Hardingham Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability. J. Neurosci., April 26, 2006; 26(17): 4509 - 4518. [Abstract] [Full Text] [PDF]

				C.-N. Wang, H.-C. Pan, Y.-L. Lin, C.-W. Chi, and Y.-J. Shiao Ester Derivatives of Tournefolic Acid B Attenuate N-Methyl-D-aspartate-Mediated Excitotoxicity in Rat Cortical Neurons Mol. Pharmacol., March 1, 2006; 69(3): 950 - 959. [Abstract] [Full Text] [PDF]

				Y. E. Kushnareva, S. E. Wiley, M. W. Ward, A. Y. Andreyev, and A. N. Murphy Excitotoxic Injury to Mitochondria Isolated from Cultured Neurons J. Biol. Chem., August 12, 2005; 280(32): 28894 - 28902. [Abstract] [Full Text] [PDF]

				R. Kovacs, J. Kardos, U. Heinemann, and O. Kann Mitochondrial Calcium Ion and Membrane Potential Transients Follow the Pattern of Epileptiform Discharges in Hippocampal Slice Cultures J. Neurosci., April 27, 2005; 25(17): 4260 - 4269. [Abstract] [Full Text] [PDF]

				J. M. Shefner, M. E. Cudkowicz, D. Schoenfeld, T. Conrad, J. Taft, M. Chilton, L. Urbinelli, M. Qureshi, H. Zhang, A. Pestronk, et al. A clinical trial of creatine in ALS Neurology, November 9, 2004; 63(9): 1656 - 1661. [Abstract] [Full Text] [PDF]

				M. B. Jekabsons and D. G. Nicholls In Situ Respiration and Bioenergetic Status of Mitochondria in Primary Cerebellar Granule Neuronal Cultures Exposed Continuously to Glutamate J. Biol. Chem., July 30, 2004; 279(31): 32989 - 33000. [Abstract] [Full Text] [PDF]

				O. Vergun, T. V. Votyakova, and I. J. Reynolds Spontaneous Changes in Mitochondrial Membrane Potential in Single Isolated Brain Mitochondria Biophys. J., November 1, 2003; 85(5): 3358 - 3366. [Abstract] [Full Text] [PDF]

				M. V. Sanchez-Gomez, E. Alberdi, G. Ibarretxe, I. Torre, and C. Matute Caspase-Dependent and Caspase-Independent Oligodendrocyte Death Mediated by AMPA and Kainate Receptors J. Neurosci., October 22, 2003; 23(29): 9519 - 9528. [Abstract] [Full Text] [PDF]

				G. L. Rintoul, A. J. Filiano, J. B. Brocard, G. J. Kress, and I. J. Reynolds Glutamate Decreases Mitochondrial Size and Movement in Primary Forebrain Neurons J. Neurosci., August 27, 2003; 23(21): 7881 - 7888. [Abstract] [Full Text] [PDF]

				T. Yamauchi, S. Kashii, H. Yasuyoshi, S. Zhang, Y. Honda, and A. Akaike Mitochondrial ATP-Sensitive Potassium Channel: A Novel Site for Neuroprotection Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2750 - 2756. [Abstract] [Full Text] [PDF]

				J. P. Vrabec, C. J. Lieven, and L. A. Levin Cell-Type-Specific Opening of the Retinal Ganglion Cell Mitochondrial Permeability Transition Pore Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2774 - 2782. [Abstract] [Full Text] [PDF]

				J. Nilsen and R. D. Brinton Mechanism of estrogen-mediated neuroprotection: Regulation of mitochondrial calcium and Bcl-2 expression PNAS, March 4, 2003; 100(5): 2842 - 2847. [Abstract] [Full Text] [PDF]

				T. L. Limke, J. K. L. Otero-Montanez, and W. D. Atchison Evidence for Interactions between Intracellular Calcium Stores during Methylmercury-Induced Intracellular Calcium Dysregulation in Rat Cerebellar Granule Neurons J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 949 - 958. [Abstract] [Full Text] [PDF]

				T. A. Sarafian, S. Kouyoumjian, F. Khoshaghideh, D. P. Tashkin, and M. D. Roth Delta 9-Tetrahydrocannabinol disrupts mitochondrial function and cell energetics Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L298 - L306. [Abstract] [Full Text] [PDF]

				D. A. Linseman, R. A. Phelps, R. J. Bouchard, S. S. Le, T. A. Laessig, M. L. McClure, and K. A. Heidenreich Insulin-Like Growth Factor-I Blocks Bcl-2 Interacting Mediator of Cell Death (Bim) Induction and Intrinsic Death Signaling in Cerebellar Granule Neurons J. Neurosci., November 1, 2002; 22(21): 9287 - 9297. [Abstract] [Full Text] [PDF]

				N. A. Riobo, M. Melani, N. Sanjuan, M. L. Fiszman, M. C. Gravielle, M. C. Carreras, E. Cadenas, and J. J. Poderoso The Modulation of Mitochondrial Nitric-oxide Synthase Activity in Rat Brain Development J. Biol. Chem., November 1, 2002; 277(45): 42447 - 42455. [Abstract] [Full Text] [PDF]

				G. Nowak Protein Kinase C-alpha and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells J. Biol. Chem., November 1, 2002; 277(45): 43377 - 43388. [Abstract] [Full Text] [PDF]

				T. F. W. HORN, G. WOLF, S. DUFFY, S. WEISS, G. KEILHOFF, and B. A. MacVICAR Nitric oxide promotes intracellular calcium release from mitochondria in striatal neurons FASEB J, October 1, 2002; 16(12): 1611 - 1622. [Abstract] [Full Text] [PDF]

				K. Ogita, H. Okuda, M. Kitano, Y. Fujinami, K. Ozaki, and Y. Yoneda Localization of Activator Protein-1 Complex with DNA Binding Activity in Mitochondria of Murine Brain after In Vivo Treatment with Kainate J. Neurosci., April 1, 2002; 22(7): 2561 - 2570. [Abstract] [Full Text] [PDF]

				S. N. Rylova, A. Amalfitano, D.-A. Persaud-Sawin, W.-X. Guo, J. Chang, P. J. Jansen, A. D. Proia, and R.-M. Boustany The CLN3 Gene is a Novel Molecular Target for Cancer Drug Discovery Cancer Res., February 1, 2002; 62(3): 801 - 808. [Abstract] [Full Text] [PDF]

				A. Almeida, J. Almeida, J. P. Bolanos, and S. Moncada Different responses of astrocytes and neurons to nitric oxide: The role of glycolytically generated ATP in astrocyte protection PNAS, December 6, 2001; (2001) 261560998. [Abstract] [Full Text] [PDF]

				S. A. Reichert, J. S. Kim-Han, and L. L. Dugan The Mitochondrial Permeability Transition Pore and Nitric Oxide Synthase Mediate Early Mitochondrial Depolarization in Astrocytes during Oxygen-Glucose Deprivation J. Neurosci., September 1, 2001; 21(17): 6608 - 6616. [Abstract] [Full Text] [PDF]

				J. F. Buckman and I. J. Reynolds Spontaneous Changes in Mitochondrial Membrane Potential in Cultured Neurons J. Neurosci., July 15, 2001; 21(14): 5054 - 5065. [Abstract] [Full Text] [PDF]

				M. Poppe, C. Reimertz, H. Du{beta}mann, A. J. Krohn, C. M. Luetjens, D. Bockelmann, A.-L. Nieminen, D. Kogel, and J. H. M. Prehn Dissipation of Potassium and Proton Gradients Inhibits Mitochondrial Hyperpolarization and Cytochrome c Release during Neural Apoptosis J. Neurosci., July 1, 2001; 21(13): 4551 - 4563. [Abstract] [Full Text] [PDF]

				A. C. Rego, M. W. Ward, and D. G. Nicholls Mitochondria Control AMPA/Kainate Receptor-Induced Cytoplasmic Calcium Deregulation in Rat Cerebellar Granule Cells J. Neurosci., March 15, 2001; 21(6): 1893 - 1901. [Abstract] [Full Text] [PDF]

				L. Tretter and V. Adam-Vizi Inhibition of Krebs Cycle Enzymes by Hydrogen Peroxide: A Key Role of {alpha}-Ketoglutarate Dehydrogenase in Limiting NADH Production under Oxidative Stress J. Neurosci., December 15, 2000; 20(24): 8972 - 8979. [Abstract] [Full Text] [PDF]

				N. Brustovetsky and J. M. Dubinsky Limitations of Cyclosporin A Inhibition of the Permeability Transition in CNS Mitochondria J. Neurosci., November 15, 2000; 20(22): 8229 - 8237. [Abstract] [Full Text] [PDF]

				D. F. Tate and E. D. Bigler Fornix and Hippocampal Atrophy in Traumatic Brain Injury Learn. Mem., November 1, 2000; 7(6): 442 - 446. [Abstract] [Full Text]

				M. W. Ward, A. C. Rego, B. G. Frenguelli, and D. G. Nicholls Mitochondrial Membrane Potential and Glutamate Excitotoxicity in Cultured Cerebellar Granule Cells J. Neurosci., October 1, 2000; 20(19): 7208 - 7219. [Abstract] [Full Text] [PDF]

				I. I. Kruman, C. Culmsee, S. L. Chan, Y. Kruman, Z. Guo, L. Penix, and M. P. Mattson Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity J. Neurosci., September 15, 2000; 20(18): 6920 - 6926. [Abstract] [Full Text] [PDF]

				C. M. Luetjens, N. T. Bui, B. Sengpiel, G. Munstermann, M. Poppe, A. J. Krohn, E. Bauerbach, J. Krieglstein, and J. H. M. Prehn Delayed Mitochondrial Dysfunction in Excitotoxic Neuron Death: Cytochrome c Release and a Secondary Increase in Superoxide Production J. Neurosci., August 1, 2000; 20(15): 5715 - 5723. [Abstract] [Full Text] [PDF]

				A. J. Gow, Q. Chen, M. Gole, M. Themistocleous, V. M.-Y. Lee, and H. Ischiropoulos Two distinct mechanisms of nitric oxide-mediated neuronal cell death show thiol dependency Am J Physiol Cell Physiol, June 1, 2000; 278(6): C1099 - C1107. [Abstract] [Full Text] [PDF]

				K. R. Hoyt, B. A. McLaughlin, D. S. Higgins Jr., and I. J. Reynolds Inhibition of Glutamate-Induced Mitochondrial Depolarization by Tamoxifen in Cultured Neurons J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 480 - 486. [Abstract] [Full Text]

				C. Chinopoulos, L. Tretter, A. Rozsa, and V. Adam-Vizi Exacerbated Responses to Oxidative Stress by an Na+ Load in Isolated Nerve Terminals: the Role of ATP Depletion and Rise of [Ca2+]i J. Neurosci., March 15, 2000; 20(6): 2094 - 2103. [Abstract] [Full Text] [PDF]

				S. Schuchmann, M. Luckermann, A. Kulik, U. Heinemann, and K. Ballanyi Ca2+- and Metabolism-Related Changes of Mitochondrial Potential in Voltage-Clamped CA1 Pyramidal Neurons In Situ J Neurophysiol, March 1, 2000; 83(3): 1710 - 1721. [Abstract] [Full Text] [PDF]

				N. Brustovetsky and J. M. Dubinsky Dual Responses of CNS Mitochondria to Elevated Calcium J. Neurosci., January 1, 2000; 20(1): 103 - 113. [Abstract] [Full Text] [PDF]

				D. G. Nicholls and S. L. Budd Mitochondria and Neuronal Survival Physiol Rev, January 1, 2000; 80(1): 315 - 360. [Abstract] [Full Text] [PDF]

				A. El Idrissi and E. Trenkner Growth Factors and Taurine Protect against Excitotoxicity by Stabilizing Calcium Homeostasis and Energy Metabolism J. Neurosci., November 1, 1999; 19(21): 9459 - 9468. [Abstract] [Full Text] [PDF]

				L. Kiedrowski Elevated Extracellular K+ Concentrations Inhibit N-Methyl-D-Aspartate-Induced Ca2+ Influx and Excitotoxicity Mol. Pharmacol., October 1, 1999; 56(4): 737 - 743. [Abstract] [Full Text]

				P. Lipton Ischemic Cell Death in Brain Neurons Physiol Rev, October 1, 1999; 79(4): 1431 - 1568. [Abstract] [Full Text] [PDF]

				L. Kiedrowski N-methyl-D-aspartate Excitotoxicity: Relationships among Plasma Membrane Potential, Na+/Ca2+ Exchange, Mitochondrial Ca2+ Overload, and Cytoplasmic Concentrations of Ca2+, H+, and K+ Mol. Pharmacol., September 1, 1999; 56(3): 619 - 632. [Abstract] [Full Text]

				B. S. Kristal and A. M. Brown Apoptogenic Ganglioside GD3 Directly Induces the Mitochondrial Permeability Transition J. Biol. Chem., August 13, 1999; 274(33): 23169 - 23175. [Abstract] [Full Text] [PDF]

				J. Lotharius, L. L. Dugan, and K. L. O'Malley Distinct Mechanisms Underlie Neurotoxin-Mediated Cell Death in Cultured Dopaminergic Neurons J. Neurosci., February 15, 1999; 19(4): 1284 - 1293. [Abstract] [Full Text] [PDF]

				M. A. Calupca, G. M. Hendricks, J. C. Hardwick, and R. L. Parsons Role of Mitochondrial Dysfunction in the Ca2+-Induced Decline of Transmitter Release at K+-Depolarized Motor Neuron Terminals J Neurophysiol, February 1, 1999; 81(2): 498 - 506. [Abstract] [Full Text] [PDF]

J. J. Lemasters V. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis Am J Physiol Gastrointest Liver Physiol, January 1, 1999; 276(1): G1 - G6. [Abstract] [Full Text] [PDF]