CALCIUM INFLUX VIA L-TYPE VOLTAGE-GATED CHANNELS MEDIATES THE DELAYED, ELEVATED INCREASES IN STEADY-STATE C-FOS MESSENGER-RNA LEVELS IN CEREBELLAR GRANULE CELLS EXPOSED TO EXCITOTOXIC LEVELS OF GLUTAMATE
R. Griffiths et al., CALCIUM INFLUX VIA L-TYPE VOLTAGE-GATED CHANNELS MEDIATES THE DELAYED, ELEVATED INCREASES IN STEADY-STATE C-FOS MESSENGER-RNA LEVELS IN CEREBELLAR GRANULE CELLS EXPOSED TO EXCITOTOXIC LEVELS OF GLUTAMATE, Journal of neuroscience research, 52(6), 1998, pp. 641-652
The altered kinetics of steady-state c-fos mRNA production in cultured
cerebellar granule cells under excitotoxic conditions was investigate
d in neurons subjected to depolarising stimuli, namely, high KCI and L
-glutamate (Glu), in which Ca2+ influx occurs by differing routes. Inc
reases in intracellular-free calcium levels ([Ca2+](i)) stimulated by
nontoxic or toxic levels of Glu were blocked by selective N-methyl-D-a
spartate (NMDA) receptor antagonism; were blocked only partially by th
e L-type channel blocker, nifedipine; and were unaffected by alpha-ami
no-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor a
ntagonists. Glu-induced cell death was prevented only by NMDA receptor
blockade, Exposure of cells to nontoxic levels of Glu resulted in a t
ransient increase in c-fos mRNA levels, whereas an excitotoxic dose pr
oduced a delay in the appearance of c-fos mRNA but a subsequent, progr
essive, and sustained (>4 hr) increase. An excitotoxic dose of Glu in
combination with either nifedipine or selective NMDA receptor antagoni
sts resulted in the normal, transient increase of c-fos mRNA levels. C
hronic exposure to 55 mM KCI caused no cytotoxicity, although it resul
ted in a delayed, elevated increase in c-fos mRNA levels that was unaf
fected by NMDA receptor blockade but reverted to the normal, transient
profile of c-fos mRNA formation when it was coadministered with nifed
ipine, The KCl-induced increase in [Ca2+](i) levels was inhibited dram
atically by nifedipine but was unaffected by any of the ionotropic Glu
receptor antagonists. The results support the notion that the appeara
nce of a delayed but elevated increase in steady-state c-fos mRNA leve
ls following exposure to excitotoxic doses of Glu is mediated specific
ally by calcium influx via L-type voltage-gated channels, (C) 1998 Wil
ey-Liss, Inc.