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Agonist‐induced desensitization of histamine Hi receptor‐mediated inositol phospholipid hydrolysis in human umbilical vein endothelial cells
Author(s) -
McCreath G.,
Hall LP.,
Hill S.J.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17067.x
Subject(s) - histamine , inositol phosphate , staurosporine , chemistry , inositol , endocrinology , medicine , protein kinase c , pertussis toxin , phospholipase c , receptor , biochemistry , biology , g protein , kinase
1 The regulation of histamine‐induced [ 3 H]‐inositol phosphate formation was studied in human cultured umbilical vein endothelial cells (HUVEC). 2 Histamine (EC50 4.8 μ m ) produced a 12.7 fold increase in [ 3 H]‐inositol phosphate formation over basal levels. Prior exposure to 0.1 m m histamine (2h) produced a 78% reduction in the response to subsequent histamine (0.1 μ m ) challenge. The IC 50 for this histamine‐induced desensitization was 0.9 μ m . 3 The inositol phosphate response to histamine (0.1 μ m ) was inhibited by phorbol dibutyrate (IC 50 40 n m ; maximal reduction 64%). This effect was antagonized by both staurosporine (100 n m ) and Ro 31–8220 (10 μ m ). However, the histamine‐induced desensitization of the H 1 ‐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 μ m ), forskolin (10 μ m ) or dibutyryl cyclic AMP (1 μ m ) had no effect upon histamine‐induced [ 3 H]‐inositol phosphate formation. 5 NaF (20 μ m ) and thrombin (EC 50 0.4 u ml −1 ) also induced inositol phosphate formation in HUVEC. Histamine pretreatment (0.1 m m , 10‐120min) failed to modify the inositol phosphate response to a subsequent NaF or thrombin challenge. 6 We conclude that the desensitization of histamine Hrreceptor‐mediated [ 3 H]‐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.