A K+ channel is involved in LPS signaling

We previously showed a clear correlation between the molecular conformation of the lipid A moiety of endotoxin molecules and their cytokine-inducing c apacity in mononuclear cells. While conically shaped lipid A moieties exhib it a high agonistic activity, a shift to a more cylindrically shaped lipid A leads to a decrease in agonistic and increase in antagonistic activity of the endotoxin molecules. Here, we show the involvement of a high-conductan ce Ca2+-activated potassium (MaxiK) channel in LPS signaling in macrophages . Corresponding to their biological activity, endotoxins activate a MaxiK c hannel as shown in outside-out patch-clamp experiments. LPS antagonists and anti-CD14 antibodies inhibit the LPS-induced activation of the channel. Bl ocking of the channel by specific channel blockers in macrophage cultures l eads to inhibition of cytokine mRNA production. In particular, this result implies that there is no other independent transmembrane signaling pathway operative in macrophages. A shift of the molecular conformation of an a pri ori antagonistic lipid A from a cylindrical to a conical shape by adding th e membrane-active compound chlorpromazine increases the activity of the Max iK channel and the biological activity of the lipid A. We conclude that the activation of the MaxiK channel is a very early step in LPS-induced signal ing in macrophages.