U-937 cells express receptors for leukotriene D4, and LTD4 stimulates receptor-mediated Ca++ mobilization with an EC50 of 5 nM. In these cells, LTE4 produces Ca++ mobilization with an EC50 of 500 nM and a maximum response that is 15 to 20% of the LTD4 response. LTE4 was shown to be a partial agonist, with a Kp of 400 nM and a linear relationship between effect and receptor occupancy, and was used as a tool to study LTD4-induced desensitization. Pretreatment of U-937 cells with LTD4 resulted in a concentration-dependent shift to the right and a decrease in the maximum of LTE4 concentration-response curves, indicating that desensitization had occurred. LTD4-induced desensitization was homologous for LTE4 and LTD4; Ca++ mobilization produced by LTB4, N-formyl-L-methionyl-L-leucyl-L-Phe and platelet-activating factor was not affected. LTD4-pretreatment produced a concentration-related desensitization of LTE4-induced Ca++ mobilization in both basal and dimethyl sulfoxide-differentiated U-937 cells. However, the maximal desensitization was greater in basal cells (66% +/- 4%) than in differentiated cells (33% +/- 7%). LTD4 pretreatment resulted in a greater percentage of reduction of Ca++ mobilization produced by LTE4 than that produced by LTD4, suggesting that a receptor reserve exists for LTD4. The extent of receptor reserve was assessed in basal and differentiated U-937 cells by comparing LTD4 concentration-response curves from control and desensitized cells.(ABSTRACT TRUNCATED AT 250 WORDS)