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

• Published in: The EMBO journal Vol. 13; no. 18; pp. 4223 - 4228
• Main Authors: Langosch, D., Laube, B., Rundström, N., Schmieden, V., Bormann, J., Betz, H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 15.09.1994
• Subjects: Animals; Biological and medical sciences; chloride channels; Chloride Channels - genetics; Chloride Channels - physiology; Chlorides - metabolism; Electric Conductivity; Genes, Dominant; Glycine - pharmacology; glycine receptors; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; hereditary diseases; Humans; hyperekplexia; Infant; man; Medical sciences; membrane currents; Mutation; Nervous system (semeiology, syndromes); Nervous System Diseases - etiology; Nervous System Diseases - genetics; Neurology; Oocytes; Receptors, Glycine - genetics; Receptors, Glycine - physiology; Reflex, Startle; RNA, Complementary - genetics; Strychnine - metabolism; Xenopus; Human; Ligand binding; Nervous system diseases; Agonist; Pathogenesis; Central nervous system; Electrophysiology; Chlorine ion; Ionic channel; Ionic current; In vitro; Cerebral disorder; Genetic disease; Glycine receptor; Central nervous system disease; Ionic conductance; Mutation; Startle epilepsy
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1002/j.1460-2075.1994.tb06742.x

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.