Fang Xiangyun, Jin Haichao, Wang Jin, Zhang Ran, Li Baobin
Department of Anesthesiology, Fudan University, Shanghai, China.
Institute for Translational Brain Research, Fudan University, Shanghai, China.
Nat Struct Mol Biol. 2025 Apr 30. doi: 10.1038/s41594-025-01542-4.
TWIK-related halothane-inhibited potassium channel (THIK1) maintains the resting membrane potential and regulates potassium efflux in microglia. It is a potential therapeutic target for neurodegenerative disorders, neuropathic pain and inflammation. However, the mechanism underlying its function remains unclear. Here we used cryo-electron microscopy to solve the structures of full-length human THIK1, revealing two inner gates and a C-type selectivity filter gate, distinct from other two-pore-domain potassium channels. One inner gate, formed by a short helix in the distal C terminus, introduces a unique gating mechanism involving the distal cytoplasmic domain. The other, beneath the selectivity filter, is constricted by Y273 in the M4 helix, dividing the cavity. In addition, the selectivity filter gate is modulated by polyunsaturated fatty acids. These structural insights into THIK1 gating, through the distal C-terminal helices, hydrophilic residues and selectivity filter, advance our understanding of THIK1's role in microglial homeostasis and neuropathologies.
TWIK相关的氟烷抑制性钾通道（THIK1）维持静息膜电位并调节小胶质细胞中的钾外流。它是神经退行性疾病、神经性疼痛和炎症的潜在治疗靶点。然而，其功能背后的机制仍不清楚。在这里，我们使用冷冻电子显微镜解析了全长人THIK1的结构，揭示了两个内部门控和一个C型选择性过滤器门控，这与其他双孔结构域钾通道不同。一个内部门控由远端C末端的短螺旋形成，引入了一种涉及远端胞质结构域的独特门控机制。另一个在选择性过滤器下方，被M4螺旋中的Y273收缩，分隔了腔室。此外，选择性过滤器门控受多不饱和脂肪酸调节。这些通过远端C末端螺旋、亲水性残基和选择性过滤器对THIK1门控的结构见解，加深了我们对THIK1在小胶质细胞稳态和神经病理学中作用的理解。
