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@ARTICLE{Rifat:268470,
      author       = {Rifat, Ali and Ossola, Bernardino and Bürli, Roland W and
                      Dawson, Lee A and Brice, Nicola L and Rowland, Anna and
                      Lizio, Marina and Xu, Xiao and Page, Keith and Fidzinski,
                      Pawel and Onken, Julia and Holtkamp, Martin and Heppner,
                      Frank L and Geiger, Jörg R P and Madry, Christian},
      title        = {{D}ifferential contribution of {THIK}-1 {K}+ channels and
                      {P}2{X}7 receptors to {ATP}-mediated neuroinflammation by
                      human microglia.},
      journal      = {Journal of neuroinflammation},
      volume       = {21},
      number       = {1},
      issn         = {1742-2094},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2024-00222},
      pages        = {58},
      year         = {2024},
      abstract     = {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.},
      keywords     = {Humans / Microglia: metabolism / NLR Family, Pyrin
                      Domain-Containing 3 Protein: metabolism / Neuroinflammatory
                      Diseases / Ion Channels: metabolism / Adenosine
                      Triphosphate: pharmacology / Adenosine Triphosphate:
                      metabolism / Receptors, Purinergic P2X7: metabolism / NLR
                      Family, Pyrin Domain-Containing 3 Protein (NLM Chemicals) /
                      Human brain (Other) / Ion channels (Other) / Microglia
                      (Other) / Neocortex (Other) / Neuroinflammation (Other) /
                      Pharmacology (Other) / Purinergic signalling (Other) / Ion
                      Channels (NLM Chemicals) / Adenosine Triphosphate (NLM
                      Chemicals) / Receptors, Purinergic P2X7 (NLM Chemicals)},
      cin          = {AG Heppner},
      ddc          = {610},
      cid          = {I:(DE-2719)1810007},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC10895799},
      pubmed       = {pmid:38409076},
      doi          = {10.1186/s12974-024-03042-6},
      url          = {https://pub.dzne.de/record/268470},
}