Human basophil histamine release is differently affected by inhibitors of calmodulin, diacylglycerol kinase and peptidyl prolyl cis-trans isomerase in a secretagogue specific manner.
To assess the role of calmodulin in human basophil histamine release, we triggered leukocytes with different secretagogues in the presence of putative inhibitors of calmodulin. Calcium ionophore-induced histamine release was reduced or blocked by calmidazolium, CGS 9343B, felodipine, metofenazate, and Ro 22-4839. H 186/86, a felodipine-related dihydropyridine derivative, blocked A23187-but not ionomycin-triggered histamine release, suggesting a difference in the mode of action of these ionophores. In contrast, leukocyte histamine release triggered by the purported protein kinase C (PKC) activator, 1,2-isopropylidene-3-decanoyl-sn-glycerol (IpOCOC9), was enhanced by calmidazolium, CGS 9349B and metofenazate but not affected by felodipine or Ro 22-4839, whereas the response triggered by 4 beta-phorbol 12-myristate 13-acetate (PMA) was reduced by metofenazate and Ro 22-4839 but not consistently affected by calmidazolium, CGS 9343B or felodipine. The PMA-induced histamine release was enhanced by H 186/86. Anti-IgE- and FMLP-induced responses were either unaffected or slightly enhanced by the examined calmodulin antagonists. In comparison with the calmodulin antagonists, R 59022, an inhibitor of diacylglycerol kinase, failed to reduce calcium ionophore-triggered histamine release, whereas FK506, an inhibitor of peptidyl prolyl cis-trans isomerase (PPI), reduced both anti-IgE- and ionophore-triggered responses. These results indicate that calmodulin constitutes an obligate link in signal transduction pathways leading to human leukocyte histamine release if the trigger is a calcium ionophore but not when responses are induced by anti-IgE, FMLP or PMA; a calmodulin-dependent component may rather balance responses induced by IpOCOC9.(ABSTRACT TRUNCATED AT 250 WORDS)
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors*; D001491:Basophils / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000502:physiology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D019852:Diacylglycerol Kinase; D015736:Felodipine / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase; D010640:Phenothiazines / Q000494:pharmacology; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D001562:Benzimidazoles; D002147:Calmodulin; D002352:Carrier Proteins; D007093:Imidazoles; D007546:Isoquinolines; D010640:Phenothiazines; D011744:Pyrimidinones; D013844:Thiazoles; C052931:Ro 22-4839; C052087:CGS 9343B; C008520:metofenazate; C031938:calmidazolium; C047505:R 59022; D010770:Phosphotransferases; D019852:Diacylglycerol Kinase; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D015736:Felodipine; D016559:Tacrolimus