TY - JOUR
T1 - NMDA receptor activation inhibits neuronal volume regulation after swelling induced by veratridine-stimulated Na+ influx in rat cortical cultures
AU - Churchwell, Kevin B.
AU - Wright, Stephen H.
AU - Emma, Francesco
AU - Rosenberg, Paul A.
AU - Strange, Kevin
PY - 1996/12/1
Y1 - 1996/12/1
N2 - Neurons and glia experience rapid fluctuations in transmembrane solute and water fluxes during normal brain activity. Cell volume must be regulated under these conditions to maintain optimal neural function. Almost nothing is known, however, about how brain cells respond to volume challenges induced by changes in transmembrane solute flux. As such, we characterized the volume- regulatory mechanisms of cultured cortical neurons swollen by veratridine- stimulated Na+ influx. Exposure of cortical neurons to 100 μM veratridine for 10-15 min caused a 1.8- to 2-fold increase in cell volume that persisted for at least 90 min. This volume increase was blocked by extracellular Na+ removal or by exposure to 5 μM tetrodotoxin, indicating that swelling is a result of Na+ entry via Na+ channels. Treatment of cells with veratridine together with various NMDA receptor antagonists had no effect on the magnitude of swelling. NMDA receptor antagonist-treated cells, however, underwent nearly complete volume recovery within 50-70 min after veratridine exposure. This recovery suggests that NMDA receptor activation disrupts neuronal osmoregulatory pathways. Volume regulation was blocked by Ba2+, quinidine, or 5-nitro-2-(3-phenylpropylamino) benzoic acid, indicating that swelling activates volume regulatory K+ and Cl- channels. Veratridine also caused a rapid, transient increase in intracellular Ca2+. Extracellular Ca2+ removal or intracellular Ca2+ chelation prevented or dramatically reduced veratridine-induced increases in intracellular Ca2+ and completely blocked volume recovery. These findings indicate that increases in Ca2+ during cell swelling induced by Na+ influx are required for activation of neuronal volume-regulatory pathways.
AB - Neurons and glia experience rapid fluctuations in transmembrane solute and water fluxes during normal brain activity. Cell volume must be regulated under these conditions to maintain optimal neural function. Almost nothing is known, however, about how brain cells respond to volume challenges induced by changes in transmembrane solute flux. As such, we characterized the volume- regulatory mechanisms of cultured cortical neurons swollen by veratridine- stimulated Na+ influx. Exposure of cortical neurons to 100 μM veratridine for 10-15 min caused a 1.8- to 2-fold increase in cell volume that persisted for at least 90 min. This volume increase was blocked by extracellular Na+ removal or by exposure to 5 μM tetrodotoxin, indicating that swelling is a result of Na+ entry via Na+ channels. Treatment of cells with veratridine together with various NMDA receptor antagonists had no effect on the magnitude of swelling. NMDA receptor antagonist-treated cells, however, underwent nearly complete volume recovery within 50-70 min after veratridine exposure. This recovery suggests that NMDA receptor activation disrupts neuronal osmoregulatory pathways. Volume regulation was blocked by Ba2+, quinidine, or 5-nitro-2-(3-phenylpropylamino) benzoic acid, indicating that swelling activates volume regulatory K+ and Cl- channels. Veratridine also caused a rapid, transient increase in intracellular Ca2+. Extracellular Ca2+ removal or intracellular Ca2+ chelation prevented or dramatically reduced veratridine-induced increases in intracellular Ca2+ and completely blocked volume recovery. These findings indicate that increases in Ca2+ during cell swelling induced by Na+ influx are required for activation of neuronal volume-regulatory pathways.
KW - MK-801
KW - edema
KW - excitotoxicity
KW - osmoregulation
UR - http://www.scopus.com/inward/record.url?scp=0029977946&partnerID=8YFLogxK
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U2 - 10.1523/jneurosci.16-23-07447.1996
DO - 10.1523/jneurosci.16-23-07447.1996
M3 - Article
C2 - 8922400
AN - SCOPUS:0029977946
SN - 0270-6474
VL - 16
SP - 7447
EP - 7457
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 23
ER -