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AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+.
J Neurochem. 1998 Jul; 71(1):112-24.JN

Abstract

Human NT2-N neurons express Ca2+-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPA-GluRs) and become vulnerable to excitotoxicity when AMPA-GluR desensitization is blocked with cyclothiazide. Although the initial increase in intracellular Ca2+ levels ([Ca2+]i) was 1.9-fold greater in the presence than in the absence of cyclothiazide, Ca2+ entry via AMPA-GluRs in an early phase of the exposure was not necessary to elicit excitotoxicity in these neurons. Rather, subsequent necrosis was caused by a >40-fold rise in [Na+]i, which induced a delayed [Ca2+]i rise. Transfer of the neurons to a 5 mM Na+ medium after AMPA-GluR activation accelerated the delayed [Ca2+]i rise and intensified excitotoxicity. Low-Na+ medium-enhanced excitotoxicity was partially blocked by amiloride or dizocilpine (MK-801), and completely blocked by removal of extracellular Ca2+, suggesting that Ca2+ entry by reverse operation of Na+/Ca2+ exchangers and via NMDA glutamate receptors was responsible for the neuronal death after excessive Na+ loading. Our results serve to emphasize the central role of neuronal Na+ loading in AMPA-GluR-mediated excitotoxicity in human neurons.

Authors+Show Affiliations

Division of Neurology, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9648857

Citation

Itoh, T, et al. "AMPA Receptor-mediated Excitotoxicity in Human NT2-N Neurons Results From Loss of Intracellular Ca2+ Homeostasis Following Marked Elevation of Intracellular Na+." Journal of Neurochemistry, vol. 71, no. 1, 1998, pp. 112-24.
Itoh T, Itoh A, Horiuchi K, et al. AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+. J Neurochem. 1998;71(1):112-24.
Itoh, T., Itoh, A., Horiuchi, K., & Pleasure, D. (1998). AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+. Journal of Neurochemistry, 71(1), 112-24.
Itoh T, et al. AMPA Receptor-mediated Excitotoxicity in Human NT2-N Neurons Results From Loss of Intracellular Ca2+ Homeostasis Following Marked Elevation of Intracellular Na+. J Neurochem. 1998;71(1):112-24. PubMed PMID: 9648857.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+. AU - Itoh,T, AU - Itoh,A, AU - Horiuchi,K, AU - Pleasure,D, PY - 1998/7/2/pubmed PY - 1998/7/2/medline PY - 1998/7/2/entrez SP - 112 EP - 24 JF - Journal of neurochemistry JO - J Neurochem VL - 71 IS - 1 N2 - Human NT2-N neurons express Ca2+-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPA-GluRs) and become vulnerable to excitotoxicity when AMPA-GluR desensitization is blocked with cyclothiazide. Although the initial increase in intracellular Ca2+ levels ([Ca2+]i) was 1.9-fold greater in the presence than in the absence of cyclothiazide, Ca2+ entry via AMPA-GluRs in an early phase of the exposure was not necessary to elicit excitotoxicity in these neurons. Rather, subsequent necrosis was caused by a >40-fold rise in [Na+]i, which induced a delayed [Ca2+]i rise. Transfer of the neurons to a 5 mM Na+ medium after AMPA-GluR activation accelerated the delayed [Ca2+]i rise and intensified excitotoxicity. Low-Na+ medium-enhanced excitotoxicity was partially blocked by amiloride or dizocilpine (MK-801), and completely blocked by removal of extracellular Ca2+, suggesting that Ca2+ entry by reverse operation of Na+/Ca2+ exchangers and via NMDA glutamate receptors was responsible for the neuronal death after excessive Na+ loading. Our results serve to emphasize the central role of neuronal Na+ loading in AMPA-GluR-mediated excitotoxicity in human neurons. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/9648857/AMPA_receptor_mediated_excitotoxicity_in_human_NT2_N_neurons_results_from_loss_of_intracellular_Ca2+_homeostasis_following_marked_elevation_of_intracellular_Na+_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=1998&volume=71&issue=1&spage=112 DB - PRIME DP - Unbound Medicine ER -