title: Histamine H2 receptor desensitization in HL-60 human promyelocytic leukemia cells.
abstract: Recent studies have suggested that cyclic AMP (cAMP) may be involved in regulation of cell growth and differentiation of cancer cells. Incubating HL-60 cells in the presence of the specific H2 agonist dimaprit resulted in 30-fold increases in cAMP levels (EC50 = 5.7 X 10(-6) M) and morphological changes suggestive of cell maturation along the granulocyte pathway. However, cells cultured with 10(-5) M dimaprit showed more than an 80% decrease in their cAMP response to subsequent addition of H2 agonists, whereas the cAMP response to prostaglandin E2 was unaltered. Desensitization was time-dependent (halftime approximately 2.5 hr with 10(-5) M dimaprit), dose-dependent (dimaprit EC50 = 1.4 X 10(-6) M) and completely prevented by 10(-3) M cimetidine. Desensitization of HL-60 cells for 4 hr with 10(-5) M dimaprit followed by the addition of 10(-3) M cimetidine resulted in total recovery of the cAMP response in less than 24 hr. The pharmacologically inactive analog N-methyldimaprit (SK&F 92054) did not increase cAMP production or cause desensitization to H2 stimulation. Desensitization was observed in the presence or absence of a phosphodiesterase inhibitor, indicating that induction of cAMP-phosphodiesterase was not involved in this process. No difference in the number of [3H]tiotidine binding sites was observed between control and dimaprit-desensitized HL-60 cells. Based on these results, we suggest that H2 receptor agonists caused an agonist-dependent desensitization, presumably due to an uncoupling of receptors from adenylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002927:Cimetidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D017259:Dimaprit; D015232:Dinoprostone; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D011458:Prostaglandins E / Q000494:pharmacology; D011968:Receptors, Histamine / Q000187:drug effects*; D011970:Receptors, Histamine H2 / Q000187:drug effects*; D013859:Thiocarbamates / Q000494:pharmacology; D013890:Thiourea / Q000494:pharmacology
chemical_list: D011458:Prostaglandins E; D011968:Receptors, Histamine; D011970:Receptors, Histamine H2; D013859:Thiocarbamates; C043202:N-methyldimaprit; D002927:Cimetidine; D006632:Histamine; D000242:Cyclic AMP; C023990:tiotidine; D013890:Thiourea; D015232:Dinoprostone; D015056:1-Methyl-3-isobutylxanthine; D017259:Dimaprit