| First Author | Rifat A | Year | 2024 |
| Journal | J Neuroinflammation | Volume | 21 |
| Issue | 1 | Pages | 58 |
| PubMed ID | 38409076 | Mgi Jnum | J:345713 |
| Mgi Id | MGI:7609200 | Doi | 10.1186/s12974-024-03042-6 |
| Citation | Rifat A, et al. (2024) Differential contribution of THIK-1 K(+) channels and P2X7 receptors to ATP-mediated neuroinflammation by human microglia. J Neuroinflammation 21(1):58 |
| abstractText | Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1beta. 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-1beta 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. |
