TY  - JOUR
AU  - Rifat, Ali
AU  - Ossola, Bernardino
AU  - Bürli, Roland W
AU  - Dawson, Lee A
AU  - Brice, Nicola L
AU  - Rowland, Anna
AU  - Lizio, Marina
AU  - Xu, Xiao
AU  - Page, Keith
AU  - Fidzinski, Pawel
AU  - Onken, Julia
AU  - Holtkamp, Martin
AU  - Heppner, Frank L
AU  - Geiger, Jörg R P
AU  - Madry, Christian
TI  - Differential contribution of THIK-1 K+ channels and P2X7 receptors to ATP-mediated neuroinflammation by human microglia.
JO  - Journal of neuroinflammation
VL  - 21
IS  - 1
SN  - 1742-2094
CY  - London
PB  - BioMed Central
M1  - DZNE-2024-00222
SP  - 58
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Microglia: metabolism
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: metabolism
KW  - Neuroinflammatory Diseases
KW  - Ion Channels: metabolism
KW  - Adenosine Triphosphate: pharmacology
KW  - Adenosine Triphosphate: metabolism
KW  - Receptors, Purinergic P2X7: metabolism
KW  - NLR Family, Pyrin Domain-Containing 3 Protein (NLM Chemicals)
KW  - Human brain (Other)
KW  - Ion channels (Other)
KW  - Microglia (Other)
KW  - Neocortex (Other)
KW  - Neuroinflammation (Other)
KW  - Pharmacology (Other)
KW  - Purinergic signalling (Other)
KW  - Ion Channels (NLM Chemicals)
KW  - Adenosine Triphosphate (NLM Chemicals)
KW  - Receptors, Purinergic P2X7 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10895799
C6  - pmid:38409076
DO  - DOI:10.1186/s12974-024-03042-6
UR  - https://pub.dzne.de/record/268470
ER  -