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


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.

SUBMITTER: Rifat A 

PROVIDER: S-EPMC10895799 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Differential contribution of THIK-1 K<sup>+</sup> channels and P2X7 receptors to ATP-mediated neuroinflammation by human microglia.

Rifat Ali A   Ossola Bernardino B   Bürli Roland W RW   Dawson Lee A LA   Brice Nicola L NL   Rowland Anna A   Lizio Marina M   Xu Xiao X   Page Keith K   Fidzinski Pawel P   Onken Julia J   Holtkamp Martin M   Heppner Frank L FL   Geiger Jörg R P JRP   Madry Christian C  

Journal of neuroinflammation 20240226 1


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<sup>+</sup> efflux as a key signaling event, suggesting that K<sup>+</sup>-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K<sup>+</sup> channels and P2X7 receptors, but their interactions and potential therapeutic role in the human b  ...[more]

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