Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia , Yerevan, Armenia.
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia , Vancouver, BC, Canada.
J Gen Physiol. 2023 May 1;155(5). doi: 10.1085/jgp.202213205. Epub 2023 Feb 21.
KCNQ1 voltage-gated K+ channels are involved in a wide variety of fundamental physiological processes and exhibit the unique feature of being markedly inhibited by external K+. Despite the potential role of this regulatory mechanism in distinct physiological and pathological processes, its exact underpinnings are not well understood. In this study, using extensive mutagenesis, molecular dynamics simulations, and single-channel recordings, we delineate the molecular mechanism of KCNQ1 modulation by external K+. First, we demonstrate the involvement of the selectivity filter in the external K+ sensitivity of the channel. Then, we show that external K+ binds to the vacant outermost ion coordination site of the selectivity filter inducing a diminution in the unitary conductance of the channel. The larger reduction in the unitary conductance compared to whole-cell currents suggests an additional modulatory effect of external K+ on the channel. Further, we show that the external K+ sensitivity of the heteromeric KCNQ1/KCNE complexes depends on the type of associated KCNE subunits.
KCNQ1 电压门控钾离子通道参与多种基本生理过程，并表现出明显受外部 K+抑制的独特特征。尽管这种调节机制在不同的生理和病理过程中可能具有潜在作用，但它的确切基础仍不清楚。在这项研究中，我们使用广泛的突变分析、分子动力学模拟和单通道记录，阐明了外部 K+调节 KCNQ1 的分子机制。首先，我们证明了选择性过滤器参与了通道对外部 K+的敏感性。然后，我们表明外部 K+结合到选择性过滤器的空最外层离子配位位，导致通道的单位电导减小。与全细胞电流相比，单位电导的减小幅度更大，表明外部 K+对通道具有额外的调节作用。此外，我们表明，异源 KCNQ1/KCNE 复合物的外部 K+敏感性取决于相关 KCNE 亚基的类型。
