Journal Article

DZNE-2024-00222

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Differential contribution of THIK-1 K+ channels and P2X7 receptors to ATP-mediated neuroinflammation by human microglia.

Rifat, A. ; Ossola, B. ; Bürli, R. W. ; Dawson, L. A. ; Brice, N. L. ; Rowland, A. ; Lizio, M. ; Xu, X. ; Page, K. ; Fidzinski, P. ; Onken, J. ; Holtkamp, M. ; Heppner, F. L.DZNE* ; Geiger, J. R. P. ; Madry, C.

2024
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s12974-024-03042-6

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.

Keyword(s): Humans (MeSH) ; Microglia: metabolism (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: metabolism (MeSH) ; Neuroinflammatory Diseases (MeSH) ; Ion Channels: metabolism (MeSH) ; Adenosine Triphosphate: pharmacology (MeSH) ; Adenosine Triphosphate: metabolism (MeSH) ; Receptors, Purinergic P2X7: metabolism (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein ; Human brain ; Ion channels ; Microglia ; Neocortex ; Neuroinflammation ; Pharmacology ; Purinergic signalling ; Ion Channels ; Adenosine Triphosphate ; Receptors, Purinergic P2X7

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Contributing Institute(s):

1. Neuroimmunology (AG Heppner)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2024

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Database coverage:
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