RT Journal Article SR Electronic T1 Changes in Agonist Concentration Dependence That Are a Function of Duration of Exposure SuggestN-Methyl-d-aspartate Receptor Nonsaturation during Synaptic Stimulation JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 212 OP 219 DO 10.1124/mol.59.2.212 VO 59 IS 2 A1 Nansheng Chen A1 Jihong Ren A1 Lynn A. Raymond A1 Timothy H. Murphy YR 2001 UL http://molpharm.aspetjournals.org/content/59/2/212.abstract AB Evidence suggests that N-methyl-d-aspartate receptors (NMDARs) have a relatively high affinity for agonist compared with non-NMDA receptors. Dose-response curves constructed with sustained agonist application suggest that the 50% effective concentration (EC50) for peak glutamate-evoked current at NMDARs is 1 to 10 μM, whereas that of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors is ∼500 μM. Given estimates of synaptic cleft glutamate concentration in the millimolar range, it would be expected that NMDARs would be saturated with agonist. However, studies of synaptic NMDAR responses indicate that these receptors may not be saturated during single release events at many synapses. To address this apparent contradiction, we have compared the glutamate dose-response curve for the peak NMDAR current generated by sustained glutamate application with that obtained during brief synaptic-like pulses of agonist. Our results using both recombinant and native NMDARs indicate a marked reduction in glutamate potency with reduced agonist application duration (EC50 = 100 to 200 μM with 1 ms application). A kinetic model suggested that the reduction in potency with shorter agonist application duration could be attributed to the relatively slow activation and deactivation rates of the NMDARs. Comparison of room temperature to 37°C indicated that NMDAR activation and deactivation were strongly accelerated by increased temperature. However, at 37°C, we still observed a significant increase in potency with longer agonist application duration. We propose that glutamate has a relatively lower potency at NMDARs than previously thought from agonist application under equilibrium conditions. This lower potency would account for data that shows nonsaturation of NMDARs during synaptic transmission.