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Decreased agonist affinity and chloride conductance of mutant glycine receptors associated with human hereditary hyperekplexia.

Langosch, D. and Laube, Bodo and Rundström, N. and Schmieden, V. and Bormann, J. and Betz, H. (1994):
Decreased agonist affinity and chloride conductance of mutant glycine receptors associated with human hereditary hyperekplexia.
In: The EMBO journal, pp. 4223-8, 13, (18), ISSN 0261-4189, [Article]

Abstract

Hereditary hyperekplexia is a dominant neurological disorder associated with point mutations at the channel-forming segment M2 of the glycine receptor alpha 1 subunit. Voltage-clamp recordings from the heterologously expressed mutants (alpha 1R271L or alpha 1R271Q) revealed 146- to 183-fold decreased potencies of glycine to activate the chloride channel, and significantly reduced maximal whole-cell currents as compared with wild-type receptors. In contrast, the ability of the competitive antagonist strychnine to block glycine-induced currents was similar in all cases. Radioligand binding assays showed a 90- to 1365-fold reduction in the ability of glycine to displace [3H]strychnine from its binding site on the mutant receptors. Paralleling the reductions in whole-cell current, the elementary main-state conductances of the mutants (alpha 1R271L, 64 pS; alpha 1R271Q, 14 pS) were lower than that of the wild-type receptor (86 pS). The decreased agonist affinities and chloride conductances of the mutants are likely to cause neural hyperexcitability of affected patients by impairing glycinergic inhibition. In addition, our data reveal that structural modifications of the ion-channel region can affect agonist binding to the glycine receptor.

Item Type: Article
Erschienen: 1994
Creators: Langosch, D. and Laube, Bodo and Rundström, N. and Schmieden, V. and Bormann, J. and Betz, H.
Title: Decreased agonist affinity and chloride conductance of mutant glycine receptors associated with human hereditary hyperekplexia.
Language: English
Abstract:

Hereditary hyperekplexia is a dominant neurological disorder associated with point mutations at the channel-forming segment M2 of the glycine receptor alpha 1 subunit. Voltage-clamp recordings from the heterologously expressed mutants (alpha 1R271L or alpha 1R271Q) revealed 146- to 183-fold decreased potencies of glycine to activate the chloride channel, and significantly reduced maximal whole-cell currents as compared with wild-type receptors. In contrast, the ability of the competitive antagonist strychnine to block glycine-induced currents was similar in all cases. Radioligand binding assays showed a 90- to 1365-fold reduction in the ability of glycine to displace [3H]strychnine from its binding site on the mutant receptors. Paralleling the reductions in whole-cell current, the elementary main-state conductances of the mutants (alpha 1R271L, 64 pS; alpha 1R271Q, 14 pS) were lower than that of the wild-type receptor (86 pS). The decreased agonist affinities and chloride conductances of the mutants are likely to cause neural hyperexcitability of affected patients by impairing glycinergic inhibition. In addition, our data reveal that structural modifications of the ion-channel region can affect agonist binding to the glycine receptor.

Journal or Publication Title: The EMBO journal
Volume: 13
Number: 18
Divisions: 10 Department of Biology
10 Department of Biology > Neurophysiology and Neurosensory Systems
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Date Deposited: 12 Apr 2011 11:23
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