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

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