Selective stimulation of excitatory amino acid receptor subtypes and the survival of cerebellar granule cells in culture: effect of kainic acid.

Our previous studies showed that the survival of cerebellar granule cells in culture is promoted by treatment with N-methyl-D-aspartate. Here we report on the influence of another glutamate analogue, kainic acid, which, in contrast to N-methyl-D-aspartate, is believed to stimulate transmitter receptors mediating fast excitatory postsynaptic potentials. The kainate effect was complex: increased survival at low concentrations (the maximum, at 25-50 microM, was about 50% promotion), whereas concentrations exceeding 50 microM resulted first in a loss of the effect, and then at concentrations of 2-5 x 10(-4) M cells became vulnerable to kainate. The trophic influence of kainate is mediated through receptors other than the N-methyl-D-aspartate preferring subtype. In contrast to the effect of N-methyl-D-aspartate, that of kainate did not depend on the medium K+ level and was potently blocked by dinitroquinoxalinedione, which--at the concentration used here--did not counteract the promotion of cell survival evoked by N-methyl-D-aspartate. Quisqualate was a potent inhibitor of the rescue by kainate. Furthermore, blockade of N-methyl-D-aspartate receptors with the selective antagonists MK-801 or aminophosphonovalerate did not inhibit, but rather potentiated the trophic effect of kainate. Possible mechanisms underlying the trophic effect of chronic depolarization or treatment with excitatory amino acids are discussed, and it is proposed that they involve elevated free cytoplasmic calcium activity following increased influx through voltage-sensitive Ca2+ channels (high K+ and kainate) or receptorgated channels (N-methyl-D-aspartate).