The slow component of the excitatory postsynaptic current in the central nervous system is generated by the activity of NMDA receptors. The activation properties of this class of glutamate receptor determine key features of the synaptic response and have important consequences for synaptic plasticity and cell physiology. NMDA receptor activation is complex and involves ligand binding, protein conformational changes, and channel blockade. Recently, two groups have proposed state models that encapsulate the essential features of NMDA receptor gating conformational changes. These models provide insight into the NMDA receptor as a molecular machine and should help us understand and manipulate NMDA receptor mediated synaptic function and pathologies.
Banke TG, Traynelis SF. 2003. Activation of NR1/NR2B NMDA receptors. Nat Neurosci6:144-152.
2.
Bekkers JM, Stevens CF. 1989. NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus. Nature341:230-233.
3.
Ciabarra AM, Sullivan JM, Gahn LG, Pecht G, Heinemann S, Sevarino KA. 1995. Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J Neurosci15:6498-6508.
4.
Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL. 1992. The time course of glutamate in the synaptic cleft. Science258:1498-1501.
5.
Cull-Candy S, Brickley S, Farrant M.2001. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol11:327-335.
6.
Curtis DR, Duggan AW, Felix D, Johnston GA, Teb Ecis AK, Watkins JC. 1972. Excitation of mammalian central neurones by acidic amino acids. Brain Res41:283-301.
7.
Dale N, Roberts A.1985. Dual-component amino-acid-mediated synaptic potentials: excitatory drive for swimming in Xenopus embryos. J Physiol363:35-59.
8.
Das S, Sasaki YF, Rothe T, Premkumar LS, Takasu M, Crandall JE, and others. 1998. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature393:377-381.
9.
Dingledine R, Borges K, Bowie D, Traynelis SF. 1999. The glutamate receptor ion channels. Pharmacol Rev51:7-61.
10.
Ebralidze AK, Rossi DJ, Tonegawa S, Slater NT. 1996. Modification of NMDA receptor channels and synaptic transmission by targeted disruption of the NR2C gene. J Neurosci16:5014-5025.
11.
Edmonds B, Gibb AJ, Colquhoun D.1995. Mechanisms of activation of glutamate receptors and the time course of excitatory synaptic currents. Annu Rev Physiol57:495-519.
12.
Forrest D, Yuzaki M, Soares HD, Ng L, Luk DC, Sheng M, and others. 1994. Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron13:325-338.
13.
Gibb AJ, Colquhoun D.1991. Glutamate activation of a single NMDA receptor-channel produces a cluster of channel openings. Proc R Soc Lond B Biol Sci243:39-45.
14.
Hille B.2001. Ion channels of excitable membranes. 3rd ed.Sunderland (MA): Sinauer.
15.
Howe JR, Colquhoun D, Cull-Candy SG. 1988. On the kinetics of large-conductance glutamate-receptor ion channels in rat cerebellar granule neurons. Proc R Soc Lond B Biol Sci233:407-422.
16.
Jahr CE. 1992. High probability opening of NMDA receptor channels by L-glutamate. Science255:470-472.
17.
Johnson JW, Ascher P.1987. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature325:529-531.
18.
Kadotani H, Hirano T, Masugi M, Nakamura K, Nakao K, Katsuki M, and others. 1996. Motor discoordination results from combined gene disruption of the NMDA receptor NR2A and NR2C subunits, but not from single disruption of the NR2A or NR2C subunit. J Neurosci16:7859-7867.
19.
Kleckner NW, Dingledine R.1988. Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science241:835-837.
20.
Kullmann DM, Asztely F, Walker MC. 2000. The role of mammalian ionotropic receptors in synaptic plasticity: LTP, LTD and epilepsy. Cell Mol Life Sci57:1551-1561.
21.
Lester RA, Clements JD, Westbrook GL, Jahr CE. 1990. Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature346:565-567.
22.
Lester RA, Jahr CE. 1992. NMDA channel behavior depends on agonist affinity. J Neurosci12:635-643.
23.
Liu DT, Tibbs GR, Paoletti P, Siegelbaum SA. 1998. Constraining ligand-binding site stoichiometry suggests that a cyclic nucleotidegated channel is composed of two functional dimers. Neuron21:235-248.
24.
Magleby KL. 2004. Modal gating of NMDA receptors. Trends Neurosci27: in press.
McIlhinney RA, Molnar E, Atack JR, Whiting PJ. 1996. Cell surface expression of the human N-methyl-D-aspartate receptor subunit 1a requires the co-expression of the NR2A subunit in transfected cells. Neuroscience70:989-997.
27.
Mohn AR, Gainetdinov RR, Caron MG, Koller BH. 1999. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell98:427-436.
28.
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. 1994. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron12:529-540.
29.
Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, and others. 1992. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science256:1217-1221.
30.
Nahum-Levy R, Lipinski D, Shavit S, Benveniste M.2001. Desensitization of NMDA receptor channels is modulated by glutamate agonists. Biophys J80:2152-2166.
31.
Patlak JB, Gration KA, Usherwood PN. 1979. Single glutamate-activated channels in locust muscle. Nature278:643-645.
32.
Patneau DK, Mayer ML. 1990. Structure-activity relationships for amino acid transmitter candidates acting at N-methyl-D-aspartate and quisqualate receptors. J Neurosci10:2385-2399.
33.
Petrenko AB, Yamakura T, Baba H, Shimoji K.2003. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg97:1108-1116.
34.
Popescu G, Auerbach A.2003. Modal gating of NMDA receptors and the shape of their synaptic response. Nat Neurosci6:476-483.
35.
Rosenmund C, Stern-Bach Y, Stevens CF. 1998. The tetrameric structure of a glutamate receptor channel. Science280:1596-1599.
36.
Sather W, Johnson JW, Henderson G, Ascher P.1990. Glycine-insensitive desensitization of NMDA responses in cultured mouse embryonic neurons. Neuron4:725-731.
37.
Seeburg PH, Burnashev N, Kohr G, Kuner T, Sprengel R, Monyer H.1995. The NMDA receptor channel: molecular design of a coincidence detector. Recent Prog Horm Res50:19-34.
38.
Sprengel R, Single FN. 1999. Mice with genetically modified NMDA and AMPA receptors. Ann N Y Acad Sci868:494-501.
39.
Verdoorn TA, Dingledine R.1988. Excitatory amino acid receptors expressed in Xenopus oocytes: agonist pharmacology. Mol Pharmacol34:298-307.
40.
Zorumski CF, Yang J, Fischbach GD. 1989. Calcium-dependent, slow desensitization distinguishes different types of glutamate receptors. Cell Mol Neurobiol9:95-104.
