GABAA Receptor Coupling Junction and Pore GABRB3 Mutations are Linked to Early-Onset Epileptic Encephalopathy
GABAA Receptor Coupling Junction and Pore GABRB3 Mutations are Linked to Early-Onset Epileptic Encephalopathy
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DOI：
10.1038/s41598-017-16010-3
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发表时间：
2017-11-21
影响因子：
4.6
通讯作者：
Macdonald, Robert L.
中科院分区：
文献类型：
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作者：
Hernandez, Ciria C.;Zhang, Yujia;Macdonald, Robert L.
GABA(A) 受体是脑抑制性氯离子通道。在这里，我们展示了在早发性癫痫性脑病 (EOEE) 和严重发育迟缓患者中发现的 GABA(A) 受体 β 3 亚基基因 (GABRB3) 中的三个从头错义突变的功能分析和结构模拟。我们试图深入了解可能将 GABA(A) 受体生物物理学和生物发生缺陷与 EOEE 患者联系起来的分子机制。突变残基是保守结构域的一部分，例如形成 GABA 结合/通道门控耦合连接和通道孔 (T288N) 的 Cys 环 (L170R) 和 M2-M3 环 (A305V)，它们在受体激活过程中功能耦合。突变的耦合连接残基在开放状态下引起重排并形成新的氢键，而突变的孔残基则重塑了孔腔。突变的偶联连接残基在激活过程中解偶联并导致功能获得，而突变的孔残基有利于低电导受体以及对地西泮的不同敏感性和功能丧失。这些数据揭示了 EOEE 相关突变影响 GABA(A) 受体功能的新分子机制。
GABA(A) receptors are brain inhibitory chloride ion channels. Here we show functional analyses and structural simulations for three de novo missense mutations in the GABA(A) receptor beta 3 subunit gene (GABRB3) identified in patients with early-onset epileptic encephalopathy (EOEE) and profound developmental delay. We sought to obtain insights into the molecular mechanisms that might link defects in GABA(A) receptor biophysics and biogenesis to patients with EOEE. The mutant residues are part of conserved structural domains such as the Cys-loop (L170R) and M2-M3 loop (A305V) that form the GABA binding/channel gating coupling junction and the channel pore (T288N), which are functionally coupled during receptor activation. The mutant coupling junction residues caused rearrangements and formation of new hydrogen bonds in the open state, while the mutant pore residue reshaped the pore cavity. Whereas mutant coupling junction residues uncoupled during activation and caused gain of function, the mutant pore residue favoured low conductance receptors and differential sensitivity to diazepam and loss of function. These data reveal novel molecular mechanisms by which EOEE-linked mutations affect GABA(A) receptor function.