Figure 8.

THIK-1 Regulates Microglial Ramification, Surveillance, and Interleukin-1β Release

Schematic showing how THIK-1 and P2Y₁₂ are central to the functions of microglia. In healthy conditions (green dashed box), tonic activity of THIK-1 maintains a negative resting membrane potential (V_m) which is essential for normal microglial ramification and surveillance of the brain (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6). When tissue damage occurs (orange box), ATP is released and converted to ADP by the ecto-ATPase CD39 (which we have not studied in this paper but which is believed to be an essential part of the mechanism by which ATP release leads to activation of P2Y₁₂). This activates P2Y₁₂, which we have shown potentiates the activity of THIK-1 (Figures 1 and 2), hyperpolarizing the membrane further. P2Y₁₂ activation evokes process outgrowth to seal off the damaged area, but this does not require THIK-1 activation (Figures 3B and 3K), and so presumably reflects the other known actions of P2Y₁₂, i.e., lowering [cAMP]_i and raising [Ca²⁺]_i (black box). Inflammasome assembly (red box) is triggered by the combination of activation of Toll-like receptor 4 (TLR4) by, for example, LPS—a priming stimulus—and activation of P2Y₁₂ (and possibly P2Y₁₃) by ATP or ADP. Loss of K⁺ from the cell and a fall of [K⁺]_i is needed for inflammasome assembly (Muñoz-Planillo et al., 2013), and this is mediated by THIK-1, since block or KO of this channel prevents the release of the inflammatory cytokine interleukin-1β (Figure 7).