The modulatory effects of spermine, histamine, and ifenprodil on recombinant N-methyl-D-aspartate (NMDA) receptors expressed from the NR1A and epsilon 4 (NR2D) subunits were studied by voltage-clamp recording in Xenopus oocytes. Spermine had no effect on responses to glutamate and glycine at NR1A/epsilon 4 receptors. None of the four previously described effects of spermine, all of which are seen at NR1A receptors and at NR1A/NR2B receptors, was seen at NR1A/epsilon 4 receptors. Similarly, NR1A/epsilon 4 receptors were insensitive to potentiation by histamine and to blockade by ifenprodil. The properties of NR1A/epsilon 4 receptors thus resemble those of NR1A/NR2C receptors and are markedly different from those of homomeric NR1A receptors. In heteromeric NR1A/epsilon 4 receptors the epsilon 4 subunit may alter properties associated with the NR1A subunit, as has been previously suggested for NR2A, NR2B, and NR2C subunits in NR1A/NR2 receptors.