Zou Guichang, Chen Qi, Chen Kai, Zuo Xin, Ge Yushu, Hou Yiwen, Pan Tao, Pan Huilin, Liu Dan, Zhang Li, Xiong Wei
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
iScience. 2019 Sep 27;19:634-646. doi: 10.1016/j.isci.2019.08.018. Epub 2019 Aug 13.
Hyperekplexia disease is usually caused by naturally occurring point mutations in glycine receptors (GlyRs). However, the γ-aminobutyric acid type A receptor (GABAR) seems to be also involved regarding the therapeutic basis for hyperekplexia using benzodiazepines, which target GABARs but not GlyRs. Here, we show that the function of GABARs was significantly impaired in the hypoglossal nucleus of hyperekplexic transgenic mice. Such impairment appeared to be mediated by interaction between GABAR and mutant GlyR. The GABAR dysfunction was caused only by mutant GlyR consisting of homomeric α 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 α-containing GABAR, a major form of pre- and extra-synaptic GABAR in the brainstem. Thus, our results suggest that the pre- and extra-synaptic GABARs could be a potential therapeutic target for hyperekplexia disease caused by GlyR mutations.
惊跳症通常由甘氨酸受体（GlyRs）中自然发生的点突变引起。然而，就使用苯二氮䓬类药物治疗惊跳症的基础而言，γ-氨基丁酸A型受体（GABAR）似乎也有涉及，苯二氮䓬类药物作用于GABAR而非GlyR。在此，我们表明，在惊跳症转基因小鼠的舌下神经核中，GABAR的功能显著受损。这种损伤似乎是由GABAR与突变型GlyR之间的相互作用介导的。GABAR功能障碍仅由主要位于突触前和突触外位点的同聚α亚基组成的突变型GlyR引起。此外，Xli-093减弱了地西泮的抢救作用，Xli-093特异性阻断了地西泮对含α的GABAR的诱导增强作用，含α的GABAR是脑干中突触前和突触外GABAR的主要形式。因此，我们的结果表明，突触前和突触外GABAR可能是由GlyR突变引起的惊跳症的潜在治疗靶点。
