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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
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Antihypertensive Agents / pharmacology
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Benzothiadiazines / pharmacology
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Calcium / metabolism*
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Calcium Channel Blockers / pharmacology
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Cell Death / drug effects
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Cell Death / physiology
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Cell Membrane / chemistry
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Cell Membrane / physiology
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Dizocilpine Maleate / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Extracellular Space / chemistry
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Extracellular Space / metabolism
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Glutamic Acid / toxicity
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Homeostasis / physiology*
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Humans
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Kainic Acid / pharmacology
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Neurons / chemistry
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Neurons / drug effects
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Neurons / metabolism*
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Neurotoxins / pharmacology
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Nimodipine / pharmacology
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Potassium / pharmacology
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Receptors, AMPA / metabolism*
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Sodium / metabolism*
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Sodium / pharmacology
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Sodium-Calcium Exchanger / metabolism
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Spider Venoms / pharmacology
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Antihypertensive Agents
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Benzothiadiazines
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Calcium Channel Blockers
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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JSTX spider toxin
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Neurotoxins
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Receptors, AMPA
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Sodium-Calcium Exchanger
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Spider Venoms
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Glutamic Acid
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Nimodipine
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Dizocilpine Maleate
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6-Cyano-7-nitroquinoxaline-2,3-dione
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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Sodium
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cyclothiazide
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Potassium
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Kainic Acid
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Calcium