9dwn | pdb_00009dwn
hTHIK1 Cryo-EM structure in GDN detergent
Structural highlights
FunctionKCNKD_HUMAN K(+) channel that conducts outward rectifying tonic currents potentiated by purinergic signals (PubMed:24163367, PubMed:25148687, PubMed:30472253, PubMed:38409076). Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties (PubMed:25148687). Contributes most of K(+) currents at the plasma membrane of resting microglia. Maintains a depolarized membrane potential required for proper ramified microglia morphology and phagocytosis, selectively mediating microglial pruning of presynaptic compartments at hippocampal excitatory synapses (PubMed:38409076). Upon local release of ATP caused by neuronal injury or infection, it is potentiated by P2RY12 and P2RX7 receptor signaling and contributes to ATP-triggered K(+) efflux underlying microglial NLRP3 inflammasome assembly and IL1B release (By similarity) (PubMed:38409076).[UniProtKB:Q8R1P5][1] [2] [3] [4] Publication Abstract from PubMedTHIK1 tandem pore domain (K2P) potassium channels regulate microglial surveillance of the central nervous system and responsiveness to inflammatory insults. With microglia recognized as critical to the pathogenesis of neurodegenerative diseases, THIK1 channels are putative therapeutic targets to control microglia dysfunction. While THIK channels can principally be distinguished from other K2Ps by their distinctive inhibitory response to volatile anesthetics (VAs), molecular details governing THIK channel gating remain largely unexplored. Here, we report a 3.2 A cryo-electron microscopy structure of the THIK1 channel in a closed conformation. A central pore gate located directly below the THIK1 selectivity filter is formed by inward-facing TM4 helix tyrosine residues that occlude the ion conduction pathway. VA inhibition of THIK requires closure of this central pore gate. Using a combination of anesthetic photolabeling, electrophysiology, and molecular dynamics simulation, we identify a functionally critical THIK1 VA binding site positioned between the central gate and a structured section of the THIK1 TM2/TM3 loop. Our results demonstrate the molecular architecture of the THIK1 channel and elucidate critical structural features involved in regulation of THIK1 channel gating and anesthetic inhibition. The cryo-EM structure and physical basis for anesthetic inhibition of the THIK1 K2P channel.,Riel EB, Bu W, Joseph TT, Khajoueinejad L, Eckenhoff RG, Riegelhaupt PM Proc Natl Acad Sci U S A. 2025 Apr 8;122(14):e2421654122. doi: , 10.1073/pnas.2421654122. Epub 2025 Apr 3. PMID:40178898[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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