Differential desensitization of functional adrenergic receptors in normal and malignant myeloid cells: relationship to receptor-mediated hormone cytotoxicity.
Malignant myeloid leukemic cells and normal macrophages and granulocytes have functional beta-adrenergic receptors, which have been quantitated by radioreceptor binding with the beta-adrenergic antagonist [(3)H]dihydroalprenolol and by induction of cyclic AMP by adrenergic hormones. Both the normal and leukemic cells have beta(2)-adrenergic receptors, and the [(3)H]dihydroalprenolol binding was saturable, reversible, and stereospecific. The leukemic cells consisted of clones that could be induced to differentiate (MGI(+)D(+)) and clones that could not be induced to differentiate to mature macrophages and granulocytes by the protein inducer MGI. The different types of leukemic clones all had 1100-2300 receptor sites per cell, whereas normal macrophages had 7000 receptors per cell. The differentiation of MGI(+)D(+) leukemic cells was associated with an increase in receptors to a number similar to that found with normal macrophages. MGI(+)D(+) leukemic cells and normal macrophages were able to densensitize to the beta-adrenergic agonist (-)isoproterenol, shown by termination of cyclic AMP induction within 10-15 min and the lack of a second induction. The leukemic cells that could not be induced to differentiate lacked this capacity for desensitization, possibly due to an alteration in the uncoupling system between the receptor and adenylate cyclase. The lack of desensitization in these leukemic cells was associated with a higher sensitivity to the receptor-mediated cytotoxic effects of adrenergic hormones. It is suggested that cells, like some leukemic cells, that are unable to desensitize to adrenergic and possibly other hormones may be appropriate targets for differential destruction by hormones under conditions that do not affect normally desensitizing cells.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000633:toxicity; D000526:Alprenolol / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004361:Drug Tolerance; D006098:Granulocytes / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism* / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D011941:Receptors, Adrenergic / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; D000526:Alprenolol; D000262:Adenylyl Cyclases