Human basophil histamine release is differently affected by inhibitors of calmodulin, diacylglycerol kinase and peptidyl prolyl cis‐trans isomerase in a secretagogue specific manner

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Abstract
Bergstrand H, Lundquist B. 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, l, 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 4β‐phorbol 12‐myristate 13‐aeetate (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. We also conclude that most employed stimuli, including IpOCOC9, trigger human basophil histamine release through partly distinet pathways.