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Leukotriene B4-induced homologous desensitization of calcium mobilization and phosphoinositide metabolism in U-937 cells

JD Winkler, HM Sarau, JJ Foley, S Mong and ST Crooke

Department of Molecular Pharmacology, Smith Kline & French Laboratories, King of Prussia, Pennsylvania.

Differentiated U-937 cells express leukotriene B4 (LTB4) receptors and mobilize Ca++ in response to LTB4. Using this cell line, we have characterized LTB4-induced desensitization. Prior exposure of U-937 cells to LTB4 resulted in a concentration- and time-dependent decrease in Ca++ mobilization in response to a subsequent challenge with LTB4 (EC50 = 2 nM; T1/2 = 4 min). Desensitization was temperature-dependent, occurring in cells pretreated with LTB4 at 37 degrees C but not at 4 degrees C. LTB4 pretreatment (100 nM, 30 min) decreased the maximal LTB4-induced Ca++ mobilization by 50% and increased the EC50 5-fold. After the cells were treated with LTB4, Ca++ mobilization in response to LTD4, platelet activating factor and chemotactic peptide N-formyl-L- methionyl-L-leucyl-L-phenylalanine were not decreased, suggesting that the desensitization was homologous and specific for LTB4. In U-937 cells, LTB4 and LTD4 induced concentration- and time-dependent and receptor-mediated phosphoinositide (PI) hydrolysis, which correlated with Ca++ mobilization. When U-937 cells were pretreated with LTB4, the amount of intracellular PI metabolites formed in response to LTB4 was reduced, whereas the response to LTD4 was unchanged. Examination of LTB4 membrane receptors in U-937 cells indicated that LTB4 pretreatment resulted in a 15% decrease in receptor number and a 3-fold decrease in affinity for LTB4. These results clearly demonstrate that LTB4-induced Ca++ mobilization and PI metabolism can be desensitized by prior exposure to LTB4 and that the mechanism of desensitization may involve altered affinity in agonist binding to the receptor.

Volume 246, Issue 1, pp. 204-210, 07/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics




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