Leukotriene D4 (LTD4) activates charybdotoxin-sensitive and -insensitive K+ channels in Ehrlich ascites tumor cells

The putative role for ATP, UTP, bradykinin and leukotriene D4 (LTD4) in the activation of the charybdotoxin-insensitive, volume-activated K+ leak pathway has been assessed in Ehrlich cells. K+ channel activity is evaluated from bumetanide-insensitive 86Rb+ efflux using Rb+ as a tracer for K+. Addition of the Ca2+-mobilizing agonists bradykinin, ATP, UTP or LTD4 accelerates the regulatory volume decrease (RVD) response and activates a fast bumetanide-insensitive, charybdotoxin-sensitive efflux of K+. In addition LTD4 activates a charybdotoxin-insensitive K+ efflux, whereas bradykinin, ATP and UTP do not. The charybdotoxin-insensitive K+ efflux dominates after addition of LTD4 at concentrations too low to elicit an increase in [Ca2+]i but still high enough to be effective in accelerating the RVD response. The EC50 values for LTD4-induced K+ effluxes are estimated at 2 nM and 15 nM for the charybdotoxin-insensitive and charybdotoxin-sensitive components, respectively. The LTD4 (cysLT1) receptor antagonist L660,711(MK-571) blocks the activation of the charybdotoxin-sensitive but not the charybdotoxin-insensitive K+ efflux. Thus, LTD4 activates two different K+ leak pathways in Ehrlich cells, one pathway activated by an increase in [Ca2+]i and the other via an alternative signalling pathway. LTD4 is thus a potential candidate for an autocrine messenger activating the Ca2+-independent, charybdotoxin-insensitive K+ channel during the RVD response in Ehrlich cells.