9ft7
From Proteopedia
Structure of the human two pore domain potassium ion channel THIK-1 (K2P13.1) in a closed conformation
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 PubMedTHIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K(+) channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-A-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower 'Y gate' that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function. Cryo-EM structure of the human THIK-1 K2P K(+) channel reveals a lower Y gate regulated by lipids and anesthetics.,Rodstrom KEJ, Eymsh B, Proks P, Hayre MS, Cordeiro S, Mendez-Otalvaro E, Madry C, Rowland A, Kopec W, Newstead S, Baukrowitz T, Schewe M, Tucker SJ Nat Struct Mol Biol. 2025 Feb 26. doi: 10.1038/s41594-025-01497-6. PMID:40011745[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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