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[3H]Dizocilpine Association Kinetics Distinguish Stimulatory and Inhibitory Polyamine Sites of N‐Methyl‐d‐Aspartate Receptors

Abstract: Spermine and other polyamines both stimulate and inhibit N‐methyl‐d‐aspartate receptor function, probably by interacting with two separate sites. To characterize these two actions, the effect of spermine on the binding kinetics of the channel blocker [3H]dizocilpine was studied in the presence of glutamate and glycine. Low concentrations (10 µM) of spermine increased the association and dissociation rates without modifying equilibrium binding, indicating that spermine increases the accessibility of [3H]dizocilpine to the channel by interacting with a high‐affinity, stimulatory site. At higher concentrations (1 mM), spermine markedly decreased equilibrium [3H]‐dizocilpine binding by decreasing both affinity and Bmax, indicating that spermine allosterically inhibits binding by interacting with a second, low‐affinity site. The presumed polyamine antagonists arcaine, diethylenetriamine, and 1,10‐diaminodecane completely inhibited equilibrium [3H]dizocilpine binding, probably by interacting with the inhibitory polyamine site or other sites, but not with the stimulatory polyamine site. Low concentrations (10 µM) of ifenprodil completely reversed the increase in association rate produced by spermine, whereas higher concentrations (IC50 = 123 µM) inhibited equilibrium binding, indicating that ifenprodil is both a potent antagonist of the stimulatory site and a low‐affinity ligand of the inhibitory site. The polyamine agonists spermine, spermidine, and neomycin interacted with the inhibitory site, but produced only partial inhibition of equilibrium [3H]dizocilpine binding.