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Vol. 59, Issue 2, 212-219, February 2001
Kinsmen Laboratory, Departments of Psychiatry and Physiology,
University of British Columbia, Vancouver, British Columbia, Canada
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
-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.
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