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Block of open channels of recombinant AMPA receptors and native AMPA/kainate receptors by Adamantane derivatives
Author(s) -
Magazanik L. G.,
Buldakova S. L.,
Samoilova M. V.,
Gmiro V. E.,
Mellor I. R.,
Usherwood P. N. R.
Publication year - 1997
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.1997.655ba.x
Subject(s) - kainate receptor , homomeric , ampa receptor , chemistry , receptor , adamantane , ionotropic effect , glutamate receptor , stereochemistry , biophysics , biochemistry , protein subunit , biology , organic chemistry , gene
1 The effects of two adamantane derivatives, 1‐trimethylammonio‐5‐(l‐adamantane‐methylammoniopentane dibromide) (IEM‐1460) and 1‐ammonio‐5‐(l‐adamantane‐methylammoniopentane dibromide) (IEM‐1754) on kainate‐induced currents were studied in Xenopus oocytes expressing recombinant ionotropic glutamate receptors and in freshly isolated neurones from rat hippocampal slices. 2 The adamantane derivatives caused use‐and voltage‐dependent block of open channels of recombinant AMPA receptors. This antagonism was dependent on receptor subunit composition; channels gated by recombinant, homomeric GluRl and GluR3 receptors exhibited a higher sensitivity to block than those gated by receptors containing edited GluR2 subunits. In the former cases, IEM‐1460 had an IC 50 of 1.6 μ m at a holding potential ( V h ) of −80 mV and IEM‐1754 was 3.8 times less potent than IEM‐1460. In contrast, 100 μ m IEM‐1460 inhibited responses to 100 μ m kainate of receptors containing edited GluR2 subunits by only 7.8 ± 2.4% ( n = 5 oocytes) at a V h of −80 mV. 3 Native AMPA/kainate receptors in isolated hippocampal cells were inhibited by adamantane derivatives in a use‐ and voltage‐dependent manner. This antagonism was dependent on cell type: pyramidal neurones were less sensitive to IEM‐1460 (IC 50 = 1617 μ m at V h =−80mV) than interneurones (IC 50 = 1.6 μ m at V h =−80 mV). IEM‐1460 and IEM‐1754 were equipotent when applied to pyramidal neurones, but IEM‐1754 was less potent (∼3 times) than IEM‐1460 when applied to interneurones. 4 It is concluded that the presence of the edited GluR2 subunit in recombinant AMPA receptors and native AMPA/kainate receptors inhibits channel block by organic cations and that adamantane derivatives are potentially valuable tools for identifying classes of AMPA/kainate receptors and their roles in synaptic transmission.