Dataset Information

Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABA_A Receptors.

ABSTRACT: Hyperekplexia disease is usually caused by naturally occurring point mutations in glycine receptors (GlyRs). However, the γ-aminobutyric acid type A receptor (GABA_AR) seems to be also involved regarding the therapeutic basis for hyperekplexia using benzodiazepines, which target GABA_ARs but not GlyRs. Here, we show that the function of GABA_ARs was significantly impaired in the hypoglossal nucleus of hyperekplexic transgenic mice. Such impairment appeared to be mediated by interaction between GABA_AR and mutant GlyR. The GABA_AR dysfunction was caused only by mutant GlyR consisting of homomeric α₁ subunits, which locate primarily at pre- and extra-synaptic sites. In addition, the rescue effects of diazepam were attenuated by Xli-093, which specifically blocked diazepam-induced potentiation on α₅-containing GABA_AR, a major form of pre- and extra-synaptic GABA_AR in the brainstem. Thus, our results suggest that the pre- and extra-synaptic GABA_ARs could be a potential therapeutic target for hyperekplexia disease caused by GlyR mutations.

SUBMITTER: Zou G

PROVIDER: S-EPMC6715904 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABAA Receptors.

Zou Guichang G Chen Qi Q Chen Kai K Zuo Xin X Ge Yushu Y Hou Yiwen Y Pan Tao T Pan Huilin H Liu Dan D Zhang Li L Xiong Wei W

iScience 20190813

Hyperekplexia disease is usually caused by naturally occurring point mutations in glycine receptors (GlyRs). However, the γ-aminobutyric acid type A receptor (GABAAR) seems to be also involved regarding the therapeutic basis for hyperekplexia using benzodiazepines, which target GABAARs but not GlyRs. Here, we show that the function of GABAARs was significantly impaired in the hypoglossal nucleus of hyperekplexic transgenic mice. Such impairment appeared to be med ...[more]

PMID: 31450193

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Project description:Epilepsy is a prevalent and severe neurological disorder and approximately 30% of patients are resistant to existing medications. It is of utmost importance to develop alternative therapies to treat epilepsy. Schisandrin B (SchB) is a major bioactive constituent of Schisandra chinensis (Turcz.) Baill and has multiple neuroprotective effects, sedative and hypnotic activities. In this study, we investigated the antiseizure effect of SchB in various mouse models of seizure and explored the underlying mechanisms. Pentylenetetrazole (PTZ), strychnine (STR), and pilocarpine-induced mouse seizure models were established. We showed that injection of SchB (10, 30, 60 mg/kg, i.p.) dose-dependently delayed the onset of generalized tonic-clonic seizures (GTCS), reduced the incidence of GTCS and mortality in PTZ and STR models. Meanwhile, injection of SchB (30 mg/kg, i.p.) exhibited therapeutic potential in pilocarpine-induced status epilepticus model, which was considered as a drug-resistant model. In whole-cell recording from CHO/HEK-239 cells stably expressing recombinant human GABAA receptors (GABAARs) and glycine receptors (GlyRs) and cultured hippocampal neurons, co-application of SchB dose-dependently enhanced GABA or glycine-induced current with EC50 values at around 5 μM, and application of SchB (10 μM) alone did not activate the channels in the absence of GABA or glycine. Furthermore, SchB (10 μM) eliminated both PTZ-induced inhibition on GABA-induced current (IGABA) and strychnine (STR)-induced inhibition on glycine-induced current (Iglycine). Moreover, SchB (10 μM) efficiently rescued the impaired GABAARs associated with genetic epilepsies. In addition, the homologous mutants in both GlyRs-α1(S267Q) and GABAARs-α1(S297Q)β2(N289S)γ2L receptors by site-directed mutagenesis tests abolished SchB-induced potentiation of IGABA and Iglycine. In conclusion, we have identified SchB as a natural positive allosteric modulator of GABAARs and GlyRs, supporting its potential as alternative therapies for epilepsy.

Dataset Information

Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABA_A Receptors.

Publications

Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABA<sub>A</sub> Receptors.

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