Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, A-1090, Vienna, Austria.
Department of Pathobiology of the Nervous System, Medical University of Vienna, A-1090, Vienna, Austria.
Commun Biol. 2022 Aug 3;5(1):784. doi: 10.1038/s42003-022-03720-2.
Gamma-aminobutyric acid type A receptors (GABARs) are ligand gated channels mediating inhibition in the central nervous system. Here, we identify a so far undescribed function of β-subunit homomers as proton-gated anion channels. Mutation of a single H267A in β3 subunits completely abolishes channel activation by protons. In molecular dynamic simulations of the β3 crystal structure protonation of H267 increased the formation of hydrogen bonds between H267 and E270 of the adjacent subunit leading to a pore stabilising ring formation and accumulation of Cl within the transmembrane pore. Conversion of these residues in proton insensitive ρ1 subunits transfers proton-dependent gating, thus highlighting the role of this interaction in proton sensitivity. Activation of chloride and bicarbonate currents at physiological pH changes (pH is in the range 6- 6.3) and kinetic studies suggest a physiological role in neuronal and non-neuronal tissues that express beta subunits, and thus as potential novel drug target.
γ-氨基丁酸 A 型受体（GABARs）是配体门控通道，介导中枢神经系统的抑制。在这里，我们发现β亚基同源二聚体作为质子门控阴离子通道的一个迄今未被描述的功能。β3 亚基中单个 H267A 的突变完全消除了质子对通道激活的作用。在β3 晶体结构的分子动力学模拟中，质子化 H267 增加了 H267 与相邻亚基的 E270 之间氢键的形成，导致孔稳定环的形成和氯离子在跨膜孔内的积累。这些残基在质子不敏感的 ρ1 亚基中的转换将质子依赖性门控转移，从而突出了这种相互作用在质子敏感性中的作用。氯离子和碳酸氢根电流在生理 pH 值变化（pH 值在 6-6.3 之间）时的激活以及动力学研究表明，在表达β亚基的神经元和非神经元组织中具有生理作用，因此可能成为新的药物靶点。
