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10. Voltage-dependent block of native AMPA receptor channels by dicationic compounds

Author

Tikhonov, D. B., Samoilova, M. V., Buldakova, S. L., Gmiro, V. E., and Lev Magazanik

Subjects
Kainic Acid, Patch-Clamp Techniques, musculoskeletal, neural, and ocular physiology, Pyramidal Cells, Adamantane, Diamines, Hippocampus, Membrane Potentials, Rats, Electrophysiology, Quaternary Ammonium Compounds, Kinetics, nervous system, Cations, Papers, Excitatory Amino Acid Agonists, Animals, Receptors, AMPA
Abstract

1. The kinetics of open channel block of GluR2-containing and GluR2-lacking AMPA receptors (AMPAR) by dicationic compounds (IEM-1460, IEM-1754, and IEM-1925) have been studied in rat hippocampal neurones using whole-cell patch clamp recording and concentration-jump techniques. Neurones were isolated from hippocampal slices by vibrodissociation. 2. The dicationic compounds were approximately 100 - 200 times more potent as blockers of GluR2-lacking AMPAR than as blockers of GluR2-containing AMPAR. The subunit specificity of channel block is determined by the blocking rate constant of a dicationic compound, whereas differences in unblocking rate constants account for differences in potency. 3. Hyperpolarization may decrease the block produced by IEM-1460 and IEM-1754 block due to the voltage-dependence of the unblocking rate constants for these compounds. This suggests that dicationic compounds permeate the AMPAR channel at negative membrane potentials. The effect was particularly apparent for GluR2-lacking AMPAR. These findings indicate that the presence of GluR2-subunit(s) in AMPAR hinders the binding of the cationic compounds and their permeation through the channel. 4. The most potent compound tested was IEM-1925. The presence of a phenylcyclohexyl moiety instead of an adamantane moiety, as in IEM-1460 and IEM1754, is probably responsible for the higher potency of IEM-1925. Dicationic compounds are important not only as pharmacological tools, but also as templates for the synthesis of new selective AMPAR blockers which may be potential therapeutic agents.

Published
2000

15. Characterization of AMPA receptor populations in rat brain cells by the use of subunit-specific open channel blocking drug, IEM-1460.

Author

Buldakova SL, Vorobjev VS, Sharonova IN, Samoilova MV, and Magazanik LG

Subjects
Adamantane pharmacology, Animals, Cerebellum cytology, Corpus Striatum cytology, Electrophysiology, Excitatory Amino Acid Agonists pharmacology, Hippocampus cytology, Interneurons chemistry, Interneurons drug effects, Interneurons physiology, Kainic Acid pharmacology, Membrane Potentials drug effects, Motor Cortex cytology, Rats, Rats, Wistar, Somatosensory Cortex cytology, Adamantane analogs & derivatives, Brain Chemistry drug effects, Ion Channel Gating drug effects, Receptors, AMPA antagonists & inhibitors, Receptors, AMPA physiology
Abstract

Dicationic adamantane derivative, IEM-1460, which selectively blocks GluR2-lacking, Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, was used to characterize the distribution of AMPA receptors among populations of rat brain cells. IEM-1460 inhibited kainate-induced inward currents (at -80 mV) in a dose-dependent manner. IEM-1460 concentrations producing 50% inhibition of kainate-induced current amplitude (IC50) varied greatly depending on the cell type studied. Striatal giant cholinergic interneurons and putative Bergmann glial cells isolated from the cerebellum were found to be highly sensitive to IEM-1460 block (IC50=2.6 microM), indicating the expression of GluR2-lacking AMPA receptor subtype. Among hippocampal and cortical non-pyramidal neurons, there were cell-to-cell differences in the pattern of AMPA receptor subtype expression. Some cells which are known to express AMPA receptors lacking GluR2 subunit exhibited high sensitivity of IEM-1460 block (IC50 about 1 microM) but in the others, the part of AMPA receptor population seemed to be represented by GluR2-having receptor subtype. The latter subtype was mainly expressed by pyramidal neurons isolated from hippocampus (IC50=1102 microM) and sensorimotor cortex (IC50=357 microM) which showed low affinity for IEM-1460 block. In conclusion, IEM-1460 can be utilized as an indicator of the distribution of AMPA receptor subtypes among populations of rat brain cells, and pharmacological detection of the absence of GluR2 subunit in AMPA receptor assembly can provide useful information for the interpretation of physiological events.

Published
1999
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16. The open channel blocking drug, IEM-1460, reveals functionally distinct alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors in rat brain neurons.

Author

Samoilova MV, Buldakova SL, Vorobjev VS, Sharonova IN, and Magazanik LG

Subjects
Adamantane pharmacology, Animals, Brain Chemistry physiology, Cerebellum chemistry, Cerebellum cytology, Corpus Striatum chemistry, Corpus Striatum cytology, Excitatory Amino Acid Agonists pharmacology, Hippocampus chemistry, Hippocampus cytology, Kainic Acid pharmacology, Membrane Potentials drug effects, Membrane Potentials physiology, Neurons physiology, Patch-Clamp Techniques, Rats, Rats, Wistar, Adamantane analogs & derivatives, Neurons chemistry, Receptors, AMPA antagonists & inhibitors, Receptors, AMPA physiology
Abstract

The properties of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors were examined in various cell types isolated from young rat hippocampus, striatum and cerebellum using patch-clamp and fast application techniques. A dicationic adamantane derivative, IEM-1460, reversibly inhibited kainate-induced currents. In the presence of 100 microM IEM-1460, kainate currents in striatal giant cholinergic interneurons and hippocampal non-pyramidal neurons were inhibited by 95% and 81%, respectively, at Vh = - 70 mV. Striatal GABAergic principal cells, hippocampal pyramidal neurons and cerebellar Purkinje cells had low sensitivity to IEM-1460 (inhibition by 4-15%). Analysis of averaged data from the cell types studied revealed a highly significant positive correlation (r= 0.93, P < 0.01) between percentage inhibition by 100 microM IEM-1460 and relative calcium permeability of AMPA receptors, P(Ca)/P(Na). Also, within each brain structure, the sensitivity of IEM-1460 block was lower the stronger the outward rectification of kainate currents. Some hippocampal neurons exhibited intermediate sensitivity to IEM-1460. Kainate currents were suppressed by 40% in the presence of 100 microM IEM-1460. Meanwhile, AMPA receptors in this cell type had low calcium permeability (P(Ca)/P(Na) = 0.13) and demonstrated outwardly rectifying kainate currents. The interrelation of different properties of AMPA receptors considering their assembly is discussed. The data obtained suggest that IEM-1460 may be a convenient and promising marker of native AMPA receptor assembly: it selectively inhibits Ca(2+)-permeable, GluR2-lacking AMPA receptors.

Published
1999
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