Agonist-induced desensitization of histamine H1 receptor-mediated inositol phospholipid hydrolysis in human umbilical vein endothelial cells.
1. The regulation of histamine-induced [3H]-inositol phosphate formation was studied in human cultured umbilical vein endothelial cells (HUVEC). 2. Histamine (EC50 4.8 microM) produced a 12.7 fold increase in [3H]-inositol phosphate formation over basal levels. Prior exposure to 0.1 mM histamine (2 h) produced a 78% reduction in the response to subsequent histamine (0.1 mM) challenge. The IC50 for this histamine-induced desensitization was 0.9 microM. 3. The inositol phosphate response to histamine (0.1 mM) was inhibited by phorbol dibutyrate (IC50 40 nM; maximal reduction 64%). This effect was antagonized by both staurosporine (100 nM) and Ro 31-8220 (10 microM). However, the histamine-induced desensitization of the H1-receptor-mediated inositol phosphate response was insensitive to the protein kinase inhibitors, staurosporine, Ro 31-8220, K252a and KN62. 4. Prior exposure to sodium nitroprusside (100 microM), forskolin (10 microM) or dibutyryl cyclic AMP (1 mM) had no effect upon histamine-induced [3H]-inositol phosphate formation. 5. NaF (20 mM) and thrombin (EC50 0.4 u ml-1) also induced inositol phosphate formation in HUVEC. Histamine pretreatment (0.1 mM, 10-120 min) failed to modify the inositol phosphate response to a subsequent NaF or thrombin challenge. 6. We conclude that the desensitization of histamine H1-receptor-mediated [3H]-inositol phosphate formation occurs at the level of the receptor and involves a mechanism independent of activation of protein kinase A, G, or C, or calcium calmodulin-dependent protein kinase II.
Department of Medicine, Medical School, Queen's Medical Centre, Nottingham.
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D000470:Alkaloids / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D007211:Indoles / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000502:physiology*; D012969:Sodium Fluoride / Q000494:pharmacology; D019311:Staurosporine; D014471:Umbilical Veins
D000470:Alkaloids; D007211:Indoles; D010716:Phosphatidylinositols; D011969:Receptors, Histamine H1; D009599:Nitroprusside; D005576:Colforsin; D015240:Phorbol 12,13-Dibutyrate; D006632:Histamine; D012969:Sodium Fluoride; D019311:Staurosporine; C064758:Ro 31-8220