Studies of the structure of glutamate receptor ion channels and the mechanisms of their blockade by organic cations

被引：10

作者：

L. G. Magazanik

D. B. Tikhonov

K. V. Bol'shakov

V. E. Gmiro

S. L. Buldakova

M. V. Samoilova

机构：

[1] I. M. Sechenov Inst. Evol. Physiol., Russian Academy of Sciences, 194223 St. Petersburg

[2] Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg

来源：

Neuroscience and Behavioral Physiology | 2003年 / 33卷 / 3期

基金：

英国惠康基金;

关键词：

AMPA receptors; Blockers; Glutamate receptors; NMDA receptors;

D O I：

10.1023/A:1022147230445

中图分类号：

学科分类号：

摘要：

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.

引用

页码：237 / 246

页数：9

共 42 条

[1] Bol'shakov K.V., Buldakova S.L., 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, pp. 1480-1486, (1999)
[2] Magazanik L.G., Blockade of ion channels as an approach to studying AMPA receptor subtypes, Ros. Fiziol. Zh. im. I. M. Sechenova, 84, pp. 994-1005, (1998)
[3] Magazanik L.G., Antonov S.M., Gmiro V.E., Mechanisms for the activation and blockade of glutamate-sensitive postsynaptic membranes, Biol. Membrany, 1, pp. 130-140, (1984)
[4] Magazanik L.G., Samoilova M.V., Buldakova S.L., Esin K.V., Gmiro V.E., 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, pp. 19-29, (1997)
[5] Magazanik L.G., Bol'shakov K.V., Buldakova S.L., Gmiro V.E., Dorofeeva N.A., Lukomsyaka N.Ya., Potep'eva N.N., Samoilova M.V., Tikhonov D.B., Fedorova I.M., Frolova E.V., Structural characteristics of ionotropic glutamate receptors, identified by channel blockade, Ros. Fiziol. Zh. im. I. M. Sechenova, 86, pp. 1138-1151, (2000)
[6] Antonov S.M., Johnson J.W., Lukomskaya N.Y., Potapyeva N.N., Gmiro V.E., Magazanik L.G., Novel adamantane derivatives act as blockers of open ligand-gated channels and as anticonvulsants, Mol. Pharmacol., 47, pp. 558-567, (1995)
[7] Antonov S.M., Johnson J.W., Voltage-dependent interaction of open-channel blockings molecules with gating of NMDA receptors in rat cortical neurons, J. Physiol. (London), 493, pp. 425-445, (1996)
[8] Benveniste M., Mayer M.L., Trapping of glutamate and glycine during open channel block of rat hippocampal neuron NMDA receptors by 9-aminoacridine, J. Physiol. (London), 483, pp. 367-384, (1995)
[9] Bolshakov K.V., Tikhonov D.B., Gmiro V.E., Magazanik L.G., Different arrangement of hydrophobic and nucleophilic components of channel binding sties in NMDA and AMPA receptor is revealed by channel blockade, Neurosci. Lett., 291, pp. 101-104, (2000)
[10] Brackley P.T., Bell D.R., Choi S.K., Nakanishi K., Usherwood P.N., Selective antagonism of native and cloned kainate and NMDA receptors by polyamine-containing toxins, J. Pharmacol. Exp. Ther., 266, pp. 1573-1580, (1993)

← 1 2 3 4 5 →