1. N-Methyl-D-aspartate (NMDA) receptors were expressed in Xenopus oocytes injected with rat brain RNA. The modulation of NMDA-induced currents was examined by activating protein kinase C (PKC) either directly (using phorbol esters) or indirectly (via metabotropic glutamate agonists). 2. Bath application of the PKC activator, 4-beta-phorbol-12,13-dibutyrate (PDBu) resulted in a two-fold increase in the NMDA-evoked current at all holding potentials examined (-80 to 0 mV). The inactive (alpha) stereoisomer of phorbol ester was ineffective. 3. The increase was observed under conditions that eliminate the oocyte's endogenous calcium-dependent chloride current, which often contributes to the NMDA response in oocytes. 4. The PDBu effect was specific to the NMDA subclass of glutamate receptors in that no increase was observed in the responses to two other glutamate agonists, kainate and AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid). 5. Stimulation of PKC by activation of metabotropic receptors via either quisqualate or trans-ACPD (trans-1-aminocyclopentane-1,3-dicarboxylic acid) also led to an increase in NMDA currents. 6. Both methods of enhancement induced transient effects. PDBu effects lasted 10-45 min, depending upon both dose and length of application. Quisqualate and trans-ACPD effects were shorter, lasting less than 10 min under these conditions of application. 7. Both methods of enhancement were blocked by the PKC inhibitor, staurosporine. In addition, the phorbol ester-induced enhancement of NMDA responses occluded further enhancement by quisqualate. 8. The results suggest a role for metabotropic glutamate receptors in modulation of NMDA-mediated processes.