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Binding-site mutations in the alpha1 subunit of the inhibitory glycine receptor convert the inhibitory metal ion Cu2+ into a positive modulator.

Schumann, Tanja and Grudzinska, Joanna and Kuzmin, Dmitry and Betz, Heinrich and Laube, Bodo (2009):
Binding-site mutations in the alpha1 subunit of the inhibitory glycine receptor convert the inhibitory metal ion Cu2+ into a positive modulator.
In: Neuropharmacology, pp. 310-7, 56, (1), ISSN 0028-3908, [Article]

Abstract

The divalent cation copper (Cu2+) has been shown to inhibit chloride currents mediated by the inhibitory glycine receptor (GlyR). Here, we analyzed Cu2+ inhibition of homo- and hetero-oligomeric GlyRs expressed in Xenopus oocytes. No significant differences in Cu2+ inhibitory potency were found between alpha1, alpha2 and alpha3 GlyRs as well as heteromeric alpha1beta receptors. Furthermore, GlyR alpha1 mutations known to reduce inhibition or potentiation of GlyR currents by Zn2+ had no effect on Cu2+ inhibition. However, Cu2+ was found to competitively antagonize glycine binding, suggesting that Cu2+ binds at the agonist-binding site. Mutations within the glycine-binding site of the GlyR alpha1 subunit reduced the inhibitory potency of Cu2+ and led to an up to 4-fold potentiation of glycine-elicited currents by Cu2+. Molecular dynamics simulation suggests this to be due to increased Cu2+ binding energies. Our data show that GlyR binding-site mutations can convert inhibitors of agonist binding into highly effective positive modulators.

Item Type: Article
Erschienen: 2009
Creators: Schumann, Tanja and Grudzinska, Joanna and Kuzmin, Dmitry and Betz, Heinrich and Laube, Bodo
Title: Binding-site mutations in the alpha1 subunit of the inhibitory glycine receptor convert the inhibitory metal ion Cu2+ into a positive modulator.
Language: English
Abstract:

The divalent cation copper (Cu2+) has been shown to inhibit chloride currents mediated by the inhibitory glycine receptor (GlyR). Here, we analyzed Cu2+ inhibition of homo- and hetero-oligomeric GlyRs expressed in Xenopus oocytes. No significant differences in Cu2+ inhibitory potency were found between alpha1, alpha2 and alpha3 GlyRs as well as heteromeric alpha1beta receptors. Furthermore, GlyR alpha1 mutations known to reduce inhibition or potentiation of GlyR currents by Zn2+ had no effect on Cu2+ inhibition. However, Cu2+ was found to competitively antagonize glycine binding, suggesting that Cu2+ binds at the agonist-binding site. Mutations within the glycine-binding site of the GlyR alpha1 subunit reduced the inhibitory potency of Cu2+ and led to an up to 4-fold potentiation of glycine-elicited currents by Cu2+. Molecular dynamics simulation suggests this to be due to increased Cu2+ binding energies. Our data show that GlyR binding-site mutations can convert inhibitors of agonist binding into highly effective positive modulators.

Journal or Publication Title: Neuropharmacology
Volume: 56
Number: 1
Divisions: 10 Department of Biology
10 Department of Biology > Neurophysiology and Neurosensory Systems
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Date Deposited: 11 Apr 2011 09:17
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