The mechanisms responsible for protein kinase-c (PKC) mediated potentiation of NMDA receptors are poorly understood. One hypothesis is that PKC-activation reduces the receptor's characteristic voltage-dependent Mg(2+)-blockade. Experiments performed on Xenopus oocytes expressing cloned NMDA receptors demonstrated that PKC-activation induced no change in the sensitivity of zeta 1/epsilon 3 and zeta 1/epsilon 4 receptors to Mg(2+)-blockade and, even though PKC-activation did induce a small shift in Mg2+ sensitivity for the zeta 1/epsilon 1 and zeta 1/epsilon 2 receptors, the change seen was not large enough to account for an appreciable increase in NMDA receptor activity. Baseline Mg(2+)-sensitivities and levels of PKC-mediated potentiation were also quantified for each of the di-heteromeric NMDA receptors. The order of Mg(2+)-sensitivity is zeta 1/epsilon 1 (most sensitive) > zeta 1/epsilon 2 > zeta 1/epsilon 4 > zeta 1/epsilon 3 (least sensitive). PKC-activation caused a 2-fold increase in zeta 1/epsilon 1 currents, a 4-fold increase in zeta 1/epsilon 2 currents and no change in either zeta 1/epsilon 3 or zeta 1/epsilon 4 currents. These data suggest that PKC-potentiation of the cloned di-heteromeric NMDA receptors does not involve a reduction in Mg(2+)-blockade. The di-heteromeric receptors possess varied properties in regard to PKC-potentiation and Mg(2+)-blockade which have been quantified here.