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

Dieter Langosch, Bodo Laube, Nils Rundström, Volker Schmieden, Joachim Bormann, Heinrich Betz

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

Abstract

Hereditary hyperekplexia is a dominant neurological disorder associated with point mutations at the channel forming segment M2 of the glycine receptor α1 subunit. Voltage-clamp recordings from the heterologously expressed mutants (α1(R271L) or α1(R271Q)) 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 (α1(R271L), 64 pS; α1(R271Q), 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.

Original languageEnglish
Pages (from-to)4223-4228
Number of pages6
JournalEMBO Journal
Volume13
Issue number18
DOIs
StatePublished - 1994
Externally publishedYes

Keywords

  • Agonist bindin
  • Chloride channel
  • Glycine recepter
  • Hyperekplexia
  • M2 segment

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