Department of Molecular & Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA; Biophysics Graduate Program, University of California Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biology (QB3), University of California Berkeley, Berkeley, CA 94720, USA.
Department of Molecular & Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biology (QB3), University of California Berkeley, Berkeley, CA 94720, USA.
Neuron. 2021 Sep 15;109(18):2902-2913.e4. doi: 10.1016/j.neuron.2021.07.009. Epub 2021 Aug 13.
TRAAK is a mechanosensitive two-pore domain K (K2P) channel localized to nodes of Ranvier in myelinated neurons. TRAAK deletion in mice results in mechanical and thermal allodynia, and gain-of-function mutations cause the human neurodevelopmental disorder FHEIG. TRAAK displays basal and stimulus-gated activities typical of K2Ps, but the mechanistic and structural differences between these modes are unknown. Here, we demonstrate that basal and mechanically gated openings are distinguished by their conductance, kinetics, and structure. Basal openings are low conductance, short duration, and due to a conductive channel conformation with the interior cavity exposed to the surrounding membrane. Mechanically gated openings are high conductance, long duration, and due to a channel conformation in which the interior cavity is sealed to the surrounding membrane. Our results explain how dual modes of activity are produced by a single ion channel and provide a basis for the development of state-selective pharmacology with the potential to treat disease.
TRAAK 是一种机械敏感的双孔域钾 (K2P) 通道，定位于有髓鞘神经元的郎飞结。TRAAK 在小鼠中的缺失会导致机械性和热感觉过敏，而功能获得性突变会导致人类神经发育障碍 FHEIG。TRAAK 表现出典型的 K2P 的基础和刺激门控活性，但这些模式之间的机械和结构差异尚不清楚。在这里，我们证明了基础和机械门控开放之间的区别在于其电导率、动力学和结构。基础开放是低电导、短持续时间的，并且是由于具有内部腔暴露于周围膜的传导通道构象。机械门控开放是高电导、长持续时间的，并且是由于通道构象，其中内部腔与周围膜密封。我们的结果解释了如何由单个离子通道产生两种活动模式，并为开发具有治疗疾病潜力的状态选择性药理学提供了基础。
