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 K ⁺ (K2P) 通道，位于有髓神经元中的 Ranvier 节点。小鼠中 TRAAK 缺失会导致机械和热异常性疼痛，功能获得性突变会导致人类神经发育障碍 FHEIG。TRAAK 显示 K2P 典型的基础和刺激门控活动，但这些模式之间的机制和结构差异尚不清楚。在这里，我们证明了基础开口和机械门控开口的区别在于它们的电导、动力学和结构。基底开口电导率低、持续时间短，并且由于内部空腔暴露于周围膜而形成导电通道构象。机械门控开口电导率高、持续时间长，并且由于内部空腔与周围膜密封的通道构造。我们的结果解释了单个离子通道如何产生双重活性模式，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。