Differentiating granule cells develop survival requirements in culture which can be met by treatment with high K+ or N-methyl-D-aspartate (NMDA) and, according to our recent findings, also with low concentrations of kainic acid (KA, 50 microM). We have now attempted to elucidate the mechanism(s) underlying the trophic effect of KA. KA rescue of cells was completely suppressed by blockers of voltage-sensitive calcium channels, such as nifedipine in low concentrations (5 x 10(-7) M), indicating that the promotion of cell survival is mediated through the activation of these channels by membrane depolarization. Thus the trophic influences of KA and NMDA share a common mechanism, increased Ca2+ influx (albeit through different routes), a conclusion that is supported by the observation that the effects of these agonists at concentrations causing maximal promotion of cell survival were not additive. Interactive effects involving different classes of excitatory amino acid receptors were revealed by the potentiation of the KA rescue of cells by the NMDA receptor antagonists, 2-amino 5-phosphonovalerate (APV) or (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine hydrogen maleate (MK-801), which on their own failed to promote, but rather reduced cell survival. The potentiation of the KA effect by the competitive NMDA antagonist APV was counteracted by the weak NMDA agonist, quinolinic acid. These observations suggest that KA alone has both trophic and toxic effects, the latter being mediated secondarily through an NMDA-like glutamate receptor, which is distinct from the conventional NMDA, KA and quisqualate preferring subtypes.