Home > Publications Database > Differential contribution of THIK-1 K+ channels and P2X7 receptors to ATP-mediated neuroinflammation by human microglia. > print

001     268470
005     20240403131604.0
024 7 _ |a pmc:PMC10895799
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024 7 _ |a 10.1186/s12974-024-03042-6
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037 _ _ |a DZNE-2024-00222
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Rifat, Ali
|b 0
245 _ _ |a Differential contribution of THIK-1 K+ channels and P2X7 receptors to ATP-mediated neuroinflammation by human microglia.
260 _ _ |a London
|c 2024
|b BioMed Central
336 7 _ |a article
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520 _ _ |a Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K+ efflux as a key signaling event, suggesting that K+-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K+ channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K+ conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K+ efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K+ conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K+-independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation.
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650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Microglia: metabolism
|2 MeSH
650 _ 2 |a NLR Family, Pyrin Domain-Containing 3 Protein: metabolism
|2 MeSH
650 _ 2 |a Neuroinflammatory Diseases
|2 MeSH
650 _ 2 |a Ion Channels: metabolism
|2 MeSH
650 _ 2 |a Adenosine Triphosphate: pharmacology
|2 MeSH
650 _ 2 |a Adenosine Triphosphate: metabolism
|2 MeSH
650 _ 2 |a Receptors, Purinergic P2X7: metabolism
|2 MeSH
650 _ 7 |a NLR Family, Pyrin Domain-Containing 3 Protein
|2 NLM Chemicals
650 _ 7 |a Human brain
|2 Other
650 _ 7 |a Ion channels
|2 Other
650 _ 7 |a Microglia
|2 Other
650 _ 7 |a Neocortex
|2 Other
650 _ 7 |a Neuroinflammation
|2 Other
650 _ 7 |a Pharmacology
|2 Other
650 _ 7 |a Purinergic signalling
|2 Other
650 _ 7 |a Ion Channels
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650 _ 7 |a Adenosine Triphosphate
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650 _ 7 |a Receptors, Purinergic P2X7
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700 1 _ |a Ossola, Bernardino
|b 1
700 1 _ |a Bürli, Roland W
|b 2
700 1 _ |a Dawson, Lee A
|b 3
700 1 _ |a Brice, Nicola L
|b 4
700 1 _ |a Rowland, Anna
|b 5
700 1 _ |a Lizio, Marina
|b 6
700 1 _ |a Xu, Xiao
|b 7
700 1 _ |a Page, Keith
|b 8
700 1 _ |a Fidzinski, Pawel
|b 9
700 1 _ |a Onken, Julia
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700 1 _ |a Holtkamp, Martin
|b 11
700 1 _ |a Heppner, Frank L
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700 1 _ |a Geiger, Jörg R P
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700 1 _ |a Madry, Christian
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773 _ _ |a 10.1186/s12974-024-03042-6
|g Vol. 21, no. 1, p. 58
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|p 58
|t Journal of neuroinflammation
|v 21
|y 2024
|x 1742-2094
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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