Microglia-Specific K_2P Channel THIK-1: Structure, Function, and Therapeutic Potential

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.

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.

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.

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.

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.

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.