Glutamate, the major excitatory neurotransmitter in the central nervous system, activates at least three types of channel-forming receptors defined by the selective agonists N-methyl-D-aspartate (NMDA), kainate, and quisqualate [or more selectively by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)]. Activation of the NMDA receptor requires glycine as well as NMDA or glutamate. Recent studies have provided evidence that certain polyamines potentiate the binding by NMDA receptors of glycine and the open channel blocker MK-801. To determine whether polyamines alter channel opening, we examined their effects on rat brain glutamate receptors expressed in Xenopus oocytes. Our results demonstrate that spermine potentiates the response of the NMDA receptor but has no effect on responses to kainate and quisqualate. Furthermore, spermine increases the maximum response to NMDA and glycine and acts, at least in part, by increasing the apparent affinity of the NMDA receptor/channel complex for glycine. The present findings and the fact that polyamines are a natural constituent of brain suggest that polyamines may play a role in the regulation of glutamatergic transmission.