Journal of Neurophysiology, Vol 71, Issue 6 2566-2569, Copyright © 1994 by APS

ARTICLES

Kinetics of AP5 dissociation from NMDA receptors: evidence for two identical cooperative binding sites

J. D. Clements and G. L. Westbrook
Vollum Institute, Portland, Oregon.

1. N-methyl-D-aspartate (NMDA) channels have two agonist binding sites that have similar binding rates for glutamate. However, it is not known whether the dissociation rates at these two sites, and hence their affinities, are similar. The competitive antagonist, D-2-amino-5-phosphonopentanoic acid (AP5), was used to study dissociation kinetics from NMDA receptors in outside-out patches from cultured hippocampal neurons. 2. Rapid steps from AP5 into NMDA produced currents with a sigmoidal activation time course that was limited by AP5 dissociation. Ensemble average currents were well fitted using kinetic models with two identical, cooperative antagonist binding sites per channel. The results suggest that the two NMDA binding sites have similar affinities, but that occupation of one site reduces the affinity of the other. 3. The agonist and antagonist binding kinetics are consistent with an approximately homogeneous population of NMDA channels in cultured hippocampal neurons.

This article has been cited by other articles:

				C. T. Smothers and J. J. Woodward Pharmacological Characterization of Glycine-Activated Currents in HEK 293 Cells Expressing N-Methyl-D-aspartate NR1 and NR3 Subunits J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 739 - 748. [Abstract] [Full Text] [PDF]

				M. Beato, V. Burzomato, and L. G. Sivilotti The kinetics of inhibition of rat recombinant heteromeric {alpha}1beta glycine receptors by the low-affinity antagonist SR-95531 J. Physiol., April 1, 2007; 580(1): 171 - 179. [Abstract] [Full Text] [PDF]

				Y. Liu, T. P. Wong, M. Aarts, A. Rooyakkers, L. Liu, T. W. Lai, D. C. Wu, J. Lu, M. Tymianski, A. M. Craig, et al. NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo J. Neurosci., March 14, 2007; 27(11): 2846 - 2857. [Abstract] [Full Text] [PDF]

				C.-Y. Hung, M. Covasa, R. C. Ritter, and G. A. Burns Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R642 - R651. [Abstract] [Full Text] [PDF]

				A. Kloda, J. D. Clements, R. J. Lewis, and D. J. Adams Adenosine Triphosphate Acts as Both a Competitive Antagonist and a Positive Allosteric Modulator at Recombinant N-Methyl-D-aspartate Receptors Mol. Pharmacol., June 1, 2004; 65(6): 1386 - 1396. [Abstract] [Full Text] [PDF]

				G. Lowe Flash Photolysis Reveals a Diversity of Ionotropic Glutamate Receptors on the Mitral Cell Somatodendritic Membrane J Neurophysiol, September 1, 2003; 90(3): 1737 - 1746. [Abstract] [Full Text] [PDF]

				H. M. Himmel, T. Kiss, S. J. Borvendeg, C. Gillen, and P. Illes The Arginine-Rich Hexapeptide R4W2 Is a Stereoselective Antagonist at the Vanilloid Receptor 1: A Ca2+ Imaging Study in Adult Rat Dorsal Root Ganglion Neurons J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 981 - 986. [Abstract] [Full Text] [PDF]

				J. D. Clements, A. Feltz, Y. Sahara, and G. L. Westbrook Activation Kinetics of AMPA Receptor Channels Reveal the Number of Functional Agonist Binding Sites J. Neurosci., January 1, 1998; 18(1): 119 - 127. [Abstract] [Full Text] [PDF]

				I. A. Omelchenko, C. S. Nelson, and C. N. Allen Lead Inhibition of N-Methyl-D-aspartate Receptors Containing NR2A, NR2C and NR2D Subunits J. Pharmacol. Exp. Ther., September 1, 1997; 282(3): 1458 - 1464. [Abstract] [Full Text]

				C. Li, R. W. Peoples, and F. F. Weight Mg2+ Inhibition of ATP-Activated Current in Rat Nodose Ganglion Neurons: Evidence That Mg2+ Decreases the Agonist Affinity of the Receptor J Neurophysiol, June 1, 1997; 77(6): 3391 - 3395. [Abstract] [Full Text] [PDF]

				T. A. Blanpied, F. A. Boeckman, E. Aizenman, and J. W. Johnson Trapping Channel Block of NMDA-Activated Responses By Amantadine and Memantine J Neurophysiol, January 1, 1997; 77(1): 309 - 323. [Abstract] [Full Text] [PDF]