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Secreted phospholipase A 2 potentiates glutamate‐induced calcium increase and cell death in primary neuronal cultures
Author(s) -
DeCoster Mark A.,
Lambeau Gerard,
Lazdunski Michel,
Bazan Nicolas G.
Publication year - 2002
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10131
Subject(s) - glutamate receptor , nmda receptor , calcium , calcium in biology , biology , arachidonic acid , glutamic acid , intracellular , biochemistry , channel blocker , endocrinology , receptor , medicine , pharmacology , enzyme , amino acid
Secreted phospholipases A 2 (sPLA 2 s) modulate neuronal survival and neurotransmitter release. Here we show that sPLA 2 (group III) synergistically increases glutamate‐induced cell death and intracellular calcium ([Ca 2+ ] i ) in cultured primary cortical and hippocampal neurons. Whereas 1 μM glutamate elicited transient [Ca 2+ ] i increases in all neurons that recovered 66% to baseline, 25 ng/ml sPLA 2 pretreatment resulted in sustained [Ca 2+ ] i increases, with only 5% recovery. At 250 nM glutamate, 25% of neurons failed to respond, and the average recovery time was 101 ± 12 sec; sPLA 2 increased recovery time to 158 ± 6 sec, and only 2% of cells failed to respond. Both the noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist MK‐801 and the calcium‐channel blocker cobalt inhibited this effect. Experiments with the glutamate uptake inhibitor L‐ trans ‐pyrollidine‐2,4‐dicarboxylic acid (2.5 μM) indicated that glutamate uptake sites are not a likely modulation point by sPLA 2 , whereas arachidonic acid (AA) potentiated calcium responses to glutamate. Thus the enhancement of glutamate‐induced [Ca 2+ ] i increases by sPLA 2 may be due to modulation at NMDA receptors and/or calcium channels by AA. These results indicate that sPLA 2 affects neuronal responses to both nontoxic (0.1–10 μM) and toxic (=25 μM) concentrations of glutamate, implicating this enzyme in neuronal functions in pathology. © 2002 Wiley‐Liss, Inc.