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.
August Krogh Institute, Biochemical Department, University of Copenhagen, Universitetsparken 13, DK-2100 Copenhagen O, Denmark. ekhoffmann@aki.ku.dk
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D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002034:Bumetanide / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002286:Carcinoma, Ehrlich Tumor; D018999:Charybdotoxin / Q000494:pharmacology*; D005260:Female; D007700:Kinetics; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology*; D008565:Membrane Proteins; D051379:Mice; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene; D012414:Rubidium Radioisotopes / Q000378:metabolism; D014544:Uridine Triphosphate / Q000494:pharmacology
D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D015221:Potassium Channels; D011422:Propionates; D011804:Quinolines; D018077:Receptors, Leukotriene; D012414:Rubidium Radioisotopes; D002034:Bumetanide; D018999:Charybdotoxin; C059141:verlukast; D017998:Leukotriene D4; D000255:Adenosine Triphosphate; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor; D011188:Potassium; D001920:Bradykinin; D002118:Calcium; D014544:Uridine Triphosphate