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AMPA-mediated excitotoxicity in oligodendrocytes: role for Na(+)-K(+)-Cl(-) co-transport and reversal of Na(+)/Ca(2+) exchanger.
J Neurochem. 2007 Sep; 102(6):1783-1795.JN

Abstract

We investigated the role of Na(+)-K(+)-Cl(-) co-transporter isoform 1 (NKCC1) and reversal of Na(+)/Ca(2+) exchanger (NCX(rev)) in glutamate-mediated excitotoxicity in oligodendrocytes obtained from rat spinal cords (postnatal day 6-8). An immunocytochemical characterization showed that these cultures express NKCC1 and Na(+)/Ca(2+) exchanger isoforms 1, 2, and 3 (NCX1, NCX2, NCX3). Exposing the cultures to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) plus cyclothiazide (CTZ) led to a transient rise in intracellular (), which was followed by a sustained overload, NKCC1 phosphorylation, and a NKCC1-mediated Na(+) influx. In the presence of a specific AMPA receptor inhibitor 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX), the AMPA/CTZ failed to elicit any changes in . The AMPA/CTZ-induced sustained rise led to mitochondrial Ca(2+) accumulation, release of cytochrome c from mitochondria, and cell death. The AMPA/CTZ-elicited increase, mitochondrial damage, and cell death were significantly reduced by inhibiting NKCC1 or NCX(rev). These data suggest that in cultured oligodendrocytes, activation of AMPA receptors leads to NKCC1 phosphorylation that enhances NKCC1-mediated Na(+) influx. The latter triggers NCX(rev) and NCX(rev)-mediated overload and compromises mitochondrial function and cellular viability.

Authors+Show Affiliations

Neuroscience Training Program, University of Wisconsin Medical School, Madison, Wisconsin, USADepartments of Neurosurgery, University of Wisconsin Medical School, Madison, Wisconsin, USAPhysiology, University of Wisconsin Medical School, Madison, Wisconsin, USAGraduate School of Pharmaceutical Sciences, Osaka University, Osaka, JapanDepartments of Psychiatry and Pharmacology, University of Illinois at Chicago, Illinois, USA.Neuroscience Training Program, University of Wisconsin Medical School, Madison, Wisconsin, USADepartments of Neurosurgery, University of Wisconsin Medical School, Madison, Wisconsin, USAPhysiology, University of Wisconsin Medical School, Madison, Wisconsin, USAGraduate School of Pharmaceutical Sciences, Osaka University, Osaka, JapanDepartments of Psychiatry and Pharmacology, University of Illinois at Chicago, Illinois, USA.Neuroscience Training Program, University of Wisconsin Medical School, Madison, Wisconsin, USADepartments of Neurosurgery, University of Wisconsin Medical School, Madison, Wisconsin, USAPhysiology, University of Wisconsin Medical School, Madison, Wisconsin, USAGraduate School of Pharmaceutical Sciences, Osaka University, Osaka, JapanDepartments of Psychiatry and Pharmacology, University of Illinois at Chicago, Illinois, USA.Neuroscience Training Program, University of Wisconsin Medical School, Madison, Wisconsin, USADepartments of Neurosurgery, University of Wisconsin Medical School, Madison, Wisconsin, USAPhysiology, University of Wisconsin Medical School, Madison, Wisconsin, USAGraduate School of Pharmaceutical Sciences, Osaka University, Osaka, JapanDepartments of Psychiatry and Pharmacology, University of Illinois at Chicago, Illinois, USA.Neuroscience Training Program, University of Wisconsin Medical School, Madison, Wisconsin, USADepartments of Neurosurgery, University of Wisconsin Medical School, Madison, Wisconsin, USAPhysiology, University of Wisconsin Medical School, Madison, Wisconsin, USAGraduate School of Pharmaceutical Sciences, Osaka University, Osaka, JapanDepartments of Psychiatry and Pharmacology, University of Illinois at Chicago, Illinois, USA.Neuroscience Training Program, University of Wisconsin Medical School, Madison, Wisconsin, USADepartments of Neurosurgery, University of Wisconsin Medical School, Madison, Wisconsin, USAPhysiology, University of Wisconsin Medical School, Madison, Wisconsin, USAGraduate School of Pharmaceutical Sciences, Osaka University, Osaka, JapanDepartments of Psychiatry and Pharmacology, University of Illinois at Chicago, Illinois, USA.Neuroscience Training Program, University of Wisconsin Medical School, Madison, Wisconsin, USADepartments of Neurosurgery, University of Wisconsin Medical School, Madison, Wisconsin, USAPhysiology, University of Wisconsin Medical School, Madison, Wisconsin, USAGraduate School of Pharmaceutical Sciences, Osaka University, Osaka, JapanDepartments of Psychiatry and Pharmacology, University of Illinois at Chicago, Illinois, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17490438

Citation

Chen, Hai, et al. "AMPA-mediated Excitotoxicity in Oligodendrocytes: Role for Na(+)-K(+)-Cl(-) Co-transport and Reversal of Na(+)/Ca(2+) Exchanger." Journal of Neurochemistry, vol. 102, no. 6, 2007, pp. 1783-1795.
Chen H, Kintner DB, Jones M, et al. AMPA-mediated excitotoxicity in oligodendrocytes: role for Na(+)-K(+)-Cl(-) co-transport and reversal of Na(+)/Ca(2+) exchanger. J Neurochem. 2007;102(6):1783-1795.
Chen, H., Kintner, D. B., Jones, M., Matsuda, T., Baba, A., Kiedrowski, L., & Sun, D. (2007). AMPA-mediated excitotoxicity in oligodendrocytes: role for Na(+)-K(+)-Cl(-) co-transport and reversal of Na(+)/Ca(2+) exchanger. Journal of Neurochemistry, 102(6), 1783-1795. https://doi.org/10.1111/j.1471-4159.2007.04638.x
Chen H, et al. AMPA-mediated Excitotoxicity in Oligodendrocytes: Role for Na(+)-K(+)-Cl(-) Co-transport and Reversal of Na(+)/Ca(2+) Exchanger. J Neurochem. 2007;102(6):1783-1795. PubMed PMID: 17490438.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AMPA-mediated excitotoxicity in oligodendrocytes: role for Na(+)-K(+)-Cl(-) co-transport and reversal of Na(+)/Ca(2+) exchanger. AU - Chen,Hai, AU - Kintner,Douglas B, AU - Jones,Mathew, AU - Matsuda,Toshio, AU - Baba,Akemichi, AU - Kiedrowski,Lech, AU - Sun,Dandan, Y1 - 2007/05/08/ PY - 2007/5/11/pubmed PY - 2007/10/20/medline PY - 2007/5/11/entrez SP - 1783 EP - 1795 JF - Journal of neurochemistry JO - J Neurochem VL - 102 IS - 6 N2 - We investigated the role of Na(+)-K(+)-Cl(-) co-transporter isoform 1 (NKCC1) and reversal of Na(+)/Ca(2+) exchanger (NCX(rev)) in glutamate-mediated excitotoxicity in oligodendrocytes obtained from rat spinal cords (postnatal day 6-8). An immunocytochemical characterization showed that these cultures express NKCC1 and Na(+)/Ca(2+) exchanger isoforms 1, 2, and 3 (NCX1, NCX2, NCX3). Exposing the cultures to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) plus cyclothiazide (CTZ) led to a transient rise in intracellular (), which was followed by a sustained overload, NKCC1 phosphorylation, and a NKCC1-mediated Na(+) influx. In the presence of a specific AMPA receptor inhibitor 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX), the AMPA/CTZ failed to elicit any changes in . The AMPA/CTZ-induced sustained rise led to mitochondrial Ca(2+) accumulation, release of cytochrome c from mitochondria, and cell death. The AMPA/CTZ-elicited increase, mitochondrial damage, and cell death were significantly reduced by inhibiting NKCC1 or NCX(rev). These data suggest that in cultured oligodendrocytes, activation of AMPA receptors leads to NKCC1 phosphorylation that enhances NKCC1-mediated Na(+) influx. The latter triggers NCX(rev) and NCX(rev)-mediated overload and compromises mitochondrial function and cellular viability. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/17490438/AMPA_mediated_excitotoxicity_in_oligodendrocytes:_role_for_Na_+__K_+__Cl____co_transport_and_reversal_of_Na_+_/Ca_2+__exchanger_ L2 - https://doi.org/10.1111/j.1471-4159.2007.04638.x DB - PRIME DP - Unbound Medicine ER -