Department of Biophysics and Neuroscience, Wrocław Medical University, ul. Chałubińskiego 3A, 50-368 Wrocław, Poland.
Department of Biophysics and Neuroscience, Wrocław Medical University, ul. Chałubińskiego 3A, 50-368 Wrocław, Poland; Department of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland.
Biochem Pharmacol. 2021 Jan;183:114338. doi: 10.1016/j.bcp.2020.114338. Epub 2020 Nov 13.
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 receptor where structural modeling indicated interaction between N-terminal αF14 and βF31 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.
五聚体配体门控离子通道（pLGICs）在电化学信号转导中至关重要，但它们的激活的确切分子机制仍不清楚。到目前为止，主要的研究重点集中在配体结合位点和通道门之间的自上而下的分子途径上。然而，最近的研究表明，pLGIC 的激活与膜平面上的亚基协调扭曲有关。这表明亚基相互作用起着关键作用，但潜在的机制在很大程度上仍然未知。在本文中，我们研究了 GABA 受体的“外围”亚基界面区域，结构建模表明 N 端 αF14 和 βF31 残基之间存在相互作用。我们的实验强调了这种相互作用在配体结合和门控中的关键作用，特别是预激活和开放，表明发生在自上而下途径之外（上方）的亚基串扰可以强烈参与受体激活。因此，这里描述的亚基相互作用似乎跨越了特别长的距离，影响了大分子的大部分。
