Effects of Kainic Acid in Rat Brain Synaptosomes: The Involvement of Calcium

Abstract

The effects of kainic acid were investigated in preparations of rat brain synaptosomes. It was found that kainic acid inhibited competitively the uptake of D-[3H]aspartate, with a Ki of approximately 0.3 mM. Kainic acid also caused release of two excitatory amino acid neurotransmitters, aspartate and glutamate, in a time- and concentration-dependent manner, but had no effect on the content of gamma-aminobutyric acid. Concomitant with the release of aspartate and glutamate, depolarization of the synaptosomal membrane and an increase in intracellular calcium were observed, with no measurable change in the concentration of internal sodium ions. The increase in intrasynaptosomal calcium and decrease in transmembrane electrical potential were prevented by the addition of glutamate, whereas the kainate-induced release of radioactive aspartate was substantially inhibited by lowering the concentration of calcium in the external medium. It is postulated that kainic acid reacts with a class of glutamate receptors located in a subpopulation of synaptosomes, presumably derived from the glutamatergic and aspartatergic neuronal pathways, which possesses high-affinity uptake system(s) for glutamate and/or aspartate. Activation of these receptors causes opening of calcium channels, influx of calcium into the synaptosomes, and depolarization of the synaptosomal plasma membrane with consequent release of amino acid neurotransmitters.

N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro

“…In several tissues, KA causes a net release of endogenous Glu and aspartate (Asp; Ferkany et al, 1982;Krespan et al, 1982;Ferkany and Coyle, 1983a,b;Pastuszko et al, 1984;Poli et al, 1985). In some cases, KA may enhance synaptic release of EAAs by stimulating presynaptic receptors (Cox and Bradford, 1978;Ferkany et al, 1982;Krespan et al, 1982;Collins et al, 1983;Coyle, 1983;Ferkany and Coyle, 1983a;Pastuszko et al, 1984;Young et al, 1988).…”

“…In several tissues, KA causes a net release of endogenous Glu and aspartate (Asp; Ferkany et al, 1982;Krespan et al, 1982;Ferkany and Coyle, 1983a,b;Pastuszko et al, 1984;Poli et al, 1985). In some cases, KA may enhance synaptic release of EAAs by stimulating presynaptic receptors (Cox and Bradford, 1978;Ferkany et al, 1982;Krespan et al, 1982;Collins et al, 1983;Coyle, 1983;Ferkany and Coyle, 1983a;Pastuszko et al, 1984;Young et al, 1988). However, there is also evidence that KAinduced blockade of Glu/Asp uptake can be a primary event in producing an increase in extracellular Glu and Asp (Lakshamanan et al, 1974;McGeer et al, 1978;Johnston et al, 1979;Krespan and Padmanaban, 1982;Pastuszko et al, 1984).…”

“…In some cases, KA may enhance synaptic release of EAAs by stimulating presynaptic receptors (Cox and Bradford, 1978;Ferkany et al, 1982;Krespan et al, 1982;Collins et al, 1983;Coyle, 1983;Ferkany and Coyle, 1983a;Pastuszko et al, 1984;Young et al, 1988). However, there is also evidence that KAinduced blockade of Glu/Asp uptake can be a primary event in producing an increase in extracellular Glu and Asp (Lakshamanan et al, 1974;McGeer et al, 1978;Johnston et al, 1979;Krespan and Padmanaban, 1982;Pastuszko et al, 1984). Along these lines, one recent report in cerebrocortical synaptosomes presented evidence for a slow leak of Glu or Asp and showed that KA could potentiate this Caz+-independent net efflux of Glu and Asp apparently by inhibiting reuptake; in that system, KA did not affect Caz+-dependent synaptic release of endogenous Glu (Pocock et al, 1988).…”

Kainic Acid Inhibits the Synaptosomal Plasma Membrane Glutamate Carrier and Allows Glutamate Leakage from the Cytoplasm but Does Not Affect Glutamate Exocytosis

“…The reported presynaptic effects of kainic acid are complex and confusing. It is generally agreed that kainic acid in the 0.1-1 mMrange inhibits the uptake of L-glutamate, D-aspartate, and L-aspartate into synaptosomes (Johnston et al, 1979;Krespan et al, 1982;Pastuszko et al, 1984;Poli et al, 1985). In addition, preincubation of brain slices or synapto-somes with kainate causes a net release of endogenous glutamate and aspartate (Krespan et al, 1982;Ferkany and Coyle, 1983;Pastuszko et al, 1984;Poli et al, 1985).…”

Herpes simplex virus vectors overexpressing the glucose transporter gene protect against seizure-induced neuron loss.

“…The finding that GT overexpression in the dentate leads to neuroprotection in the CA3 cell field was also surprising, but it agrees with our current understanding of hippocampal circuitry and KA actions. Granule neurons from all parts of the dentate give rise to multiple collateral projections to the pyramidal neurons of the CA3 (27), and KA neurotoxicity in the CA3 depends on these intact projections (28,29), because KA triggers release of EAAs by dentate axon terminals (30)(31)(32) and/or disrupts EAA reuptake at such terminals (33,34). Energy depletion leads to membrane depolarization and calcium-dependent release of EAAs and ultimately the reversal of the EAA/Na+-cotransporter (35), which results in both increased EAA release and decreased reuptake.…”