Microglia‐Specific K 2P Channel THIK ‐1: Structure, Function, and Therapeutic Potential

ABSTRACT Background The tandem pore domain halothane‐inhibited potassium (THIK‐1) channel is a member of the two‐pore domain potassium (K2P) channel family and plays a critical role in maintaining the resting membrane potential. THIK‐1 has emerged as a key regulator of microglial physiology and neuroimmune signaling. With the rapid accumulation of structural, electrophysiological, and functional evidence, there is an increasing need for an integrated understanding of THIK‐1 in the context of microglial biology and disease. Aims This review provides a comprehensive synthesis of the structural, regulatory, and functional properties of THIK‐1, with a particular focus on its roles in microglial physiology, neuroimmune signaling, and central nervous system (CNS) pathologies. Materials and Methods We conducted a comprehensive review of recent literature, including electrophysiological, molecular, and structural studies, with particular emphasis on cryo‐electron microscopy findings, pharmacological modulation, and disease‐associated functional analyses. Results THIK‐1 is selectively enriched in microglia and contributes to essential cellular processes, including surveillance motility, synaptic pruning, and inflammasome activation. Its high constitutive activity makes it a dominant determinant of the microglial membrane potential. Structural studies have identified key features, including a lipid‐interacting pocket and a cytoplasmic gate, which underlie lipid‐ and anesthetic‐mediated regulation. Functionally, THIK‐1‐mediated K⁺ efflux is required for NOD‐like receptor pyrin domain‐containing protein 3 (NLRP3) inflammasome activation and pyroptosis. Accumulating evidence links THIK‐1 to major CNS disorders, including neuroinflammation, neurodegeneration (e.g., Alzheimer's and Parkinson's diseases), and psychiatric disorders. Discussion The convergence of structural, electrophysiological, and immunological findings positions THIK‐1 as a central regulator of neuroimmune signaling. Integration of these findings provides new insights into how ion channel activity shapes microglial function and disease processes. Conclusion THIK‐1 represents a critical nexus between ion channel biophysics and neuroimmune dysfunction. A comprehensive understanding of its regulation and function supports its potential as a microglia‐specific therapeutic target in neuroinflammatory and neurodegenerative disorders.