Interaction between GABA(A) receptor alpha(1) and beta(2) subunits at the N-terminal peripheral regions is crucial for receptor binding and gating

Terejko Katarzyna; Michalowski Michal A.; Dominik Anna; Andrzejczak Anna; Mozrzymas Jerzy W.

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Interaction between GABA(A) receptor alpha(1) and beta(2) subunits at the N-terminal peripheral regions is crucial for receptor binding and gating

机译：N-末端外周区域的GABA（A）受体α（1）和β（2）亚基之间的相互作用对于受体结合和门控是至关重要的

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Pentameric ligand gated ion channels (pLGICs) are crucial in electrochemical signaling but exact molecular mechanisms of their activation remain elusive. So far, major effort focused on the top-down molecular pathway between the ligand binding site and the channel gate. However, recent studies revealed that pLGIC activation is associated with coordinated subunit twisting in the membrane plane. This suggests a key role of intersubunit interactions but the underlying mechanisms remain largely unknown. Herein, we investigated a "peripheral" subunit interface region of GABA(A) receptor where structural modeling indicated interaction between N-terminal alpha(1)F14 and beta(2)F31 residues. Our experiments underscored a crucial role of this interaction in ligand binding and gating, especially preactivation and opening, showing that the intersubunit cross-talk taking place outside (above) the top-down pathway can be strongly involved in receptor activation. Thus, described here intersubunit interaction appears to operate across a particularly long distance, affecting vast portions of the macromolecule.

机译：五聚体配体门控离子通道（PLGICS）在电化学信号传导中至关重要，但其活化的精确分子机制仍然难以捉摸。到目前为止，主要努力集中在配体结合位点和通道栅极之间的自上而下的分子途径。然而，最近的研究表明，综合体激活与膜平面中的协调亚基相关联。这表明IntersubUnit互动的关键作用，但基本机制仍然很大程度上是未知的。在此，我们研究了GABA（A）受体的“外周”亚基接口区域，其中结构建模在N-末端α（1）F14和β（2）F31残基之间的相互作用。我们的实验强调了这种相互作用在配体结合和门控的关键作用，特别是暂存和开口，表明在外面（上述）外部发生的intersubUnit串扰可以强烈地参与受体激活。因此，这里描述的IntersubUnit相互作用似乎在特别长的距离上运行，影响大分子的大部分。

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来源
《Biochemical Pharmacology》 |2021年第1期|共12页
作者
Terejko Katarzyna; Michalowski Michal A.; Dominik Anna; Andrzejczak Anna; Mozrzymas Jerzy W.;
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作者单位

Wroclaw Med Univ Dept Biophys &

Neurosci Ul Chalubinskiego 3A PL-50368 Wroclaw Poland;

Wroclaw Med Univ Dept Biophys &

Neurosci Ul Chalubinskiego 3A PL-50368 Wroclaw Poland;

Wroclaw Med Univ Dept Biophys &

Neurosci Ul Chalubinskiego 3A PL-50368 Wroclaw Poland;

Univ Wroclaw Dept Mol Physiol &

Neurobiol Ul Sienkiewicza 21 PL-50335 Wroclaw Poland;

Wroclaw Med Univ Dept Biophys &

Neurosci Ul Chalubinskiego 3A PL-50368 Wroclaw Poland;

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正文语种 eng
中图分类药理学;
关键词
GABA(A) receptors; Single-channel analysis; Structure-function; Mutagenesis; Homology modeling;

机译：GABA（A）受体;单通道分析;结构功能;诱变;同源性建模;

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2. Analysis of the Conservation of T Cell Receptor Alpha and Beta Chain Variable Regions Gene in pp65 Peptide-Specific HLA-A*0201-Restricted CD8+ T Cells [J] . Wei Luo, Li Ma, Qian Wen, 中国免疫学杂志（英文版） . 2009,第002期
3. Two conserved arginines in the extracellular N-terminal domain of the GABA(A) receptor alpha(5) subunit are crucial for receptor function. [J] . Hartvig L, Lukensmejer B, Liljefors T, Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry . 2000,第4期

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Interaction between GABA(A) receptor alpha(1) and beta(2) subunits at the N-terminal peripheral regions is crucial for receptor binding and gating

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