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A K+ channel is involved in LPS signaling

Division of Biophysics, Research Center Borstel, Borstel, Germany, useydel{at}fz-borstel.de

O. Scheel

Division of Biophysics, Research Center Borstel, Borstel, Germany

M. Müller

Division of Biophysics, Research Center Borstel, Borstel, Germany

K. Brandenburg

Division of Biophysics, Research Center Borstel, Borstel, Germany

R. Blunck

Division of Biophysics, Research Center Borstel, Borstel, Germany

We previously showed a clear correlation between the molecular conformation of the lipid A moiety of endotoxin molecules and their cytokine-inducing capacity in mononuclear cells. While conically shaped lipid A moieties exhibit 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-conductance Ca²⁺-activated potassium (MaxiK) channel in LPS signaling in macrophages. Corresponding to their biological activity, endotoxins activate a MaxiK channel as shown in outside-out patch-clamp experiments. LPS antagonists and anti-CD14 antibodies inhibit the LPS-induced activation of the channel. Blocking of the channel by specific channel blockers in macrophage cultures leads 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 priori antagonistic lipid A from a cylindrical to a conical shape by adding the membrane-active compound chlorpromazine increases the activity of the MaxiK 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 signaling in macrophages.

Journal of Endotoxin Research, Vol. 7, No. 3, 243-247 (2001)
DOI: 10.1177/09680519010070030901


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