Abstract
The structural determinants for blockade of the AMPA and NMDA subtypes of glutamate receptors were studied by analysis of structural-functional relationships in a series of mono- and dicationic compounds. The results showed that the hydrophobic and nucleophilic components of the blocker binding sites are located close to each other in the channel of the NMDA receptor, while they are spatially distant in the channel of the AMPA receptor. Molecular mechanical methods were used to construct models of these channels satisfying these topographic criteria and providing adequate descriptions of the binding of the channel blockers. According to the models, binding of blockers to the NMDA channel occurs in the selective filter of the channel (the N/Q/R site). The nucleophilic region of the AMPA channel is formed by the oxygen atoms of glycine residues in position +2 relative to the selective filter. Identification of the major relationships between the molecular structure of the ion channels of these glutamate receptor subtypes and their blockade by organic cations allows the further synthesis of AMPA and NMDA channel blockers with specified levels of activity and selectivity to be directed.
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REFERENCES
K. V. Bol'shakov and S. L. Buldakova, “Comparison of the subunit composition and splice variants of AMPA receptors in neurons of hippocampal field CA1 and the dentate fascia,” Ros. Fiziol. Zh. im. I. M. Sechenova, 85, 1480–1486 (1999).
L. G. Magazanik, “Blockade of ion channels as an approach to studying AMPA receptor subtypes,” Ros. Fiziol. Zh. im. I. M. Sechenova, 84, 994–1005 (1998).
L. G. Magazanik,, S. M. Antonov, and V. E. Gmiro, “Mechanisms for the activation and blockade of glutamate-sensitive postsynaptic membranes,” Biol. Membrany, 1, 130–140 (1984).
L. G. Magazanik, M. V. Samoilova, S. L. Buldakova, K. V. Esin, and V. E. Gmiro, “Selective inhibition of AMPA/kainate receptors of hippocampal interneurons as a new approach to studying inhibitory systems,” Ros. Fiziol. Zh. im. I. M. Sechenova, 83, 19–29 (1997).
L. G. Magazanik, K. V. Bol'shakov, S. L. Buldakova, V. E. Gmiro, N. A. Dorofeeva, N. Ya. Lukomskaya, N. N. Potep'eva, M. V. Samoilova, D. B. Tikhonov, I. M. Fedorova, and E. V. Frolova, “Structural characteristics of ionotropic glutamate receptors, identified by channel blockade,” Ros. Fiziol. Zh. im. I. M. Sechenova, 86, 1138–1151 (2000).
S. M. Antonov, J. W. Johnson, N. Y. Lukomskaya, N. N. Potapyeva, V. E. Gmiro, and L. G. Magazanik, “Novel adamantane derivatives act as blockers of open ligand-gated channels and as anticonvulsants,” Mol. Pharmacol., 47, 558–567 (1995).
S. M. Antonov and J. W. Johnson, “Voltage-dependent interaction of open-channel blockings molecules with gating of NMDA receptors in rat cortical neurons,” J. Physiol. (London), 493, 425–445 (1996).
M. Benveniste and M. L. Mayer, “Trapping of glutamate and glycine during open channel block of rat hippocampal neuron NMDA receptors by 9-aminoacridine,” J. Physiol. (London), 483, 367–384 (1995).
K. V. Bolshakov, D. B. Tikhonov, V. E. Gmiro, and L. G. Magazanik, “Different arrangement of hydrophobic and nucleophilic components of channel binding sties in NMDA and AMPA receptor is revealed by channel blockade,” Neurosci. Lett., 291, 101–104 (2000).
P. T. Brackley, D. R. Bell, S. K. Choi, K. Nakanishi, and P. N. Usherwood, “Selective antagonism of native and cloned kainate and NMDA receptors by polyamine-containing toxins,” J. Pharmacol. Exp. Ther., 266, 1573–1580 (1993).
S. L. Buldakova, V. S. Vorobjev, I. N. Sharonova, M. V. Samoilova, and L. G. Magazanik, “Characterization of AMPA receptor populations in rat brain cells by the use of subunit-specific open channel blocking drug, IÉM-1640,” Brain Res., 94, 261–268 (1999).
N. Burnashev, Z. Zhou, E. Neher, and B. Sakmann, “Fractional calcium currents through recombinant GluR channels of the NMDA, AMPA and kainate receptor subtypes,” J. Physiol. (London), 485, 403–418 (1995).
N. Burnashev, A. Villaroel, and B. Sakmann, “Dimensions and ion selectivity of recombinant AMPA and kainate receptor channels and their dependence on R/O site residues,” J. Physiol. (London), 496, 165–173 (1996).
R. Dingledine, R. I. Hume, and S. Heinemann, “Structural determinants of barium permeation and rectification in non-NMDA glutamate receptor channels,” J. Neurosci., 12, 4080–4087 (1992).
R. Dingledine, K. Borges, D. Bowie, S. F. Traynelis, “The glutamate receptor ion channels,” Pharmacol. Rev., 51, 8–61 (1999).
D. A. Doyle, J. M. Cabral, R. A. Pfuetzner, A. Kuo, J. M. Gulbis, S. L. Cohen, B. T. Chait, and R. MacKinnon, “The structure of the potassium channel: basis of K+ conduction and selectivity,” Science, 280, 69–77 (1998).
A. V. Ferrer-Montiel, J. M. Merino, R. Planells-Cases, W. Sun, and M. Montal, “Structural determinants of the blocker binding site in glutamate and NMDA receptor channels,” Neuropharmacology, 37, 139–147 (1998).
M. Frerking and R. A. Nicoll, “Synaptic kainate receptors,” Curr. Opin. Neurobiol., 10, 342–351 (2000).
J. R. P. Geiger, T. Melcher, D. S. Koh, B. Sakmann, P. H. Seeburg, P. Jonas, and H. Monyer, “Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS,” Neuron, 15, 193–204 (1995).
S. Herlitze, M. Raditsch, J. P. Ruppersberg, W. Jahn, H. Monyer, R. Schoepfer, and V. Witzemann, “Agriotoxin detects molecular differences in AMPA receptor channels,” Neuron, 10, 1131–1140 (1993).
T. Isa, M. Iino, and S. Ozawa, “Spermine blocks synaptic transmission mediated by Ca2+-permeable AMPA receptors,” Neuroreport, 7, 689–692 (1996).
Z. Li and H. A. Scheraga, “Structure and free energy of complex thermodynamic systems,” J. Mol. Struct., 179, 333–352 (1988).
J. F. MacDonald, M. C. Bartlett, I. Mody, P. Pahapill, J. N. Reynolds, M. W. Salter, J. H. Schneiderman, and P. S. Pennefather, “Actions of ketamine, phenylcyclidine and MK-801 on NMDA receptor currents in cultured mouse hippocampal neurones,” J. Physiol. (London), 432, 483–508 (1991).
L. G. Magazanik, S. L. Buldakova, M. V. Samoilova, V. E. Gmiro, I. R. Mellor, and P. N. R. Usherwood, “Block of open channels of recombinant AMPA receptors and native AMPA/kainate receptors by adamantane derivatives,” J. Physiol. (London), 505, 655–663 (1997).
L. J. Martin, C. D. Blackstone, A. I. Levey, R. L. Huganir, and D. L. Price, “AMPA glutamate receptor subunits are differentially distributed in rat brain,” Neurosci., 53, 327–358 (1993).
H. Mori, H. Masaki, T. Yamakura, and M. Mishina, “Identification by mutagenesis of a Mg2+-block site of the NMDA receptor channel,” Nature, 358, 673–675 (1992).
C. G. Parsons, V. A. Panchenko, V. O. Pinchenko, A. Y. Tsyndrenko, and O. A. Krishtal, “Comparative patch-clamp studies with freshly dissociated rat hippocampal and striatal neurons on the NMDA receptor antagonistic effects of amantadine and memantine,” Eur. J. Neurosci., 8, 446–454 (1996).
M. V. Samoilova, S. L. Buldakova, V. S. Vorobjev, I. N. Sharonova, and L. G. Magazanik, “Open channel blocking drug, IÉM-1640, reveals functionally distinct α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in rat brain neurons,” Neurosci., 94, 261–268 (1999).
M. V. Samoilova, E. V. Frolova, N. N. Potapjeva, I. M. Fedorova, V. A. Gmiro, and L. G. Magazanik, “Channel blocking drugs as tools to study glutamate receptors in insect muscles and molluscan neurons,” Invertebr. Neurosci., 3, 117–126 (1997).
M. Sheng and D. T. Pak, “Glutamate receptor anchoring proteins and the molecular organization of excitatory synapses,” Ann. N.Y. Acad. Sci., 30, No. 868, 483–493 (1999).
A. I. Sobolevsky, S. G. Koshelev, and B. I. Khodorov, “Probing of NMDA channels with fast blockers,” J. Neurosci., 19, 10611–10626 (1999).
G. T. Swanson, S. K. Kamboj, and S. J. Cull-Candy, “Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition,” J. Neurosci., 17, 58–69 (1997).
D. B. Tikhonov, B. S. Zhorov, and L. G. Magazanik, “Intersegment hydrogen bonds as possible structural determinants of the N/Q/R site in glutamate receptors,” Biophys. J., 77, 1914–1926 (1999).
D. B. Tikhonov, M. V. Samoilova, S. L. Buldakova, V. E. Gmiro, and L. G. Magazanik, “Voltage-dependent block of native AMPA receptor channels by dicationic compounds,” Brit. J. Pharmacol., 129, 265–2 (2000).
A. Villarroel, N. Burnashev, and B. Sakmann, “Dimensions of the narrow portion of a recombinant NMDA receptor channel,” Biophys. J., 68, 866–875 (1995).
V. S. Vorobjev, “Vibrodissociation of sliced mammalian nervous tissue,” J. Neurosci. Meth., 38, 145–150 (1991).
M. S. Washburn and R. Dingledine, “Block of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by polyamines and polyamine toxins,” J. Pharmacol. Exp. Ther., 278, 666–678 (1996).
S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Chio, G. Alagona, S. Profeta, and P. K. Weiner, “A new force field for molecular mechanical simulation of nucleic acids and proteins,” J. Amer. Chem. Assoc., 106, 765–784 (1984).
K. Williams, A. J. Pahk, K. Kashiwagi, T. Masiko, N. D. Nguyen, and K. Igarishi, “The selective filter of the N-methyl-D-aspartate receptor: a tryptophan residue controls block and permeation of Mg2+,” Mol. Pharmacol., 53, 933–941 (1998).
D. J. Wyllie, P. Behe, M. Nassar, R. Schoepfer, and D. Colquhoun, “Single-channel currents from recombinant NMDA NR1A/NR2D receptors expressed in Xenopus oocytes,” Proc. Roy. Soc., B263, 1079–1086 (1996).
B. S. Zhorov, “Vector method for calculating derivatives of energy of atom-atom interactions of complex molecules according to generalized coordinates,” J. Struct. Chem., 22, 4–8 (1981).
B. S. Zhorov and V. S. Ananthanarayanan, “Structural model of synthetic Ca2+ channel with bound Ca2+ ions and dihydropyridine ligand,” Biophys. J., 70, 22–37 (1996).
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Magazanik, L.G., Tikhonov, D.B., Bol'shakov, K.V. et al. Studies of the Structure of Glutamate Receptor Ion Channels and the Mechanisms of Their Blockade by Organic Cations. Neurosci Behav Physiol 33, 237–246 (2003). https://doi.org/10.1023/A:1022147230445
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DOI: https://doi.org/10.1023/A:1022147230445