SENSITIVITY OF THE N-METHYL-D-ASPARTATE RECEPTOR TO POLYAMINES IS CONTROLLED BY NR2 SUBUNITS

The endogenous polyamine spermine has multiple effects on the N-methyl -D-aspartate (NMDA) receptor. These include an increase in the magnitu de of NMDA-induced whole-cell currents that is seen in the presence of saturating concentrations of glycine (''glycine-independent'' stimula tion), an increase in the affinity of the receptor for glycine (''glyc ine-dependent'' stimulation), and voltage-dependent inhibition. Althou gh many of the properties of native NMDA receptors are seen with homom eric NR1 receptors expressed in Xenopus oocytes, we have found that th e effects of spermine are differentially regulated by NR2 subunits in heteromeric NR1/NR2 receptors. Glycine-independent stimulation by sper mine occurred at homomeric NR1A receptors, which lack the amino-termin al insert in NR1, and at heteromeric NR1A/NR2B receptors but not at he teromeric NR1A/ NR2A or NR1A/NR2C receptors. Glycine-independent stimu lation was not seen at homomeric NR1B receptors, which include the ami no-terminal insert in NR1, or at heteromeric receptors containing NR1B . Thus, glycine-independent stimulation by polyamines requires the pre sence of an NR1 variant, such as NR1A, that lacks the amino-terminal i nsert, but the manifestation of the stimulatory effect is controlled b y the type of NR2 subunit present in a heteromeric complex. Glycine-de pendent stimulation was seen at NR1A/NR2A and NR1A/NR2B receptors and may therefore involve a second polyamine binding site distinct from th at which produces glycine-independent stimulation. The voltage-depende nt inhibitory effect of spermine, which is more pronounced at hyperpol arized membrane potentials, occurred with similar magnitudes at NR1A/N R2A and NR1A/NR2B receptors but was absent at NR1A/NR2C receptors. Thu s, NR2 subunits control both the stimulatory and inhibitory effects of spermine at NMDA receptors. Stimulation but not inhibition by spermin e was seen at NR1A/NR2B receptors in the presence of extracellular Mg2 +. Stimulation, seen in the presence of physiological concentrations o f Ca2+ and Mg2+, may be the predominant effect of polyamines at NMDA r eceptors in the intact nervous system.