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<jats:title>Abstract</jats:title><jats:p>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<jats:sup>+</jats:sup> efflux as a key signaling event, suggesting that K<jats:sup>+</jats:sup>-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K<jats:sup>+</jats:sup>-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.</jats:p>
<jats:p><jats:bold>Graphical Abstract</jats:bold></jats:p>
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Hinweis
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DeepGreen-ID: cae1e2db69954973a825c6997418ebf8 ; metadata provieded by: DeepGreen (https://www.oa-deepgreen.de/api/v1/), LIVIVO search scope life sciences (http://z3950.zbmed.de:6210/livivo), Crossref Unified Resource API (https://api.crossref.org/swagger-ui/index.html), to.science.api (https://frl.publisso.de/), ZDB JSON-API (beta) (https://zeitschriftendatenbank.de/api/), lobid - Dateninfrastruktur für Bibliotheken (https://lobid.org/resources/search)
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