Kb. Churchwell et al., NMDA RECEPTOR ACTIVATION INHIBITS NEURONAL VOLUME REGULATION AFTER SWELLING-INDUCED BY VERATRIDINE-STIMULATED NA+ INFLUX IN RAT CORTICAL CULTURES, The Journal of neuroscience, 16(23), 1996, pp. 7447-7457
Neurons and glia experience rapid fluctuations in transmembrane solute
and water fluxes during normal brain activity, Cell volume must be re
gulated under these conditions to maintain optimal neural function. Al
most nothing is known, however, about how brain cells respond to volum
e challenges induced by changes in transmembrane solute flux, As such,
we characterized the volume-regulatory mechanisms of cultured cortica
l neurons swollen by veratridine-stimulated Na+ influx: Exposure of co
rtical neurons to 100 mu M veratridine for 10-15 min caused a 1,8- to
2-fold increase in cell volume that persisted for at least 90 min. Thi
s volume increase was blocked by extracellular Na+ removal or by expos
ure to 5 mu M 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, underwe
nt nearly complete volume recovery within 50-70 min after veratridine
exposure. This recovery suggests that NMDA receptor activation disrupt
s neuronal osmoregulatory pathways. Volume regulation was blocked by B
a2-. quinidine, or 5-nitro-2-(3-phenylpropylamino) benzoic acid, indic
ating that swelling activates volume regulatory K+ and Cl- channels, V
eratridine also caused a rapid, transient increase in intracellular Ca
2+. Extracellular Ca2+ removal or intracellular Ca2+ chelation prevent
ed or dramatically reduced veratridine-induced increases in intracellu
lar Ca2+ and completely blocked volume recovery. These findings indica
te that increases in Ca2+ during cell swelling induced by Na+ influx a
re required for activation of neuronal volume-regulatory pathways.