Reher, Till M. and Neumann, Detlef and Buschauer, Armin and Seifert, Roland (2012) Incomplete activation of human eosinophils via the histamine H(4)-receptor: Evidence for ligand-specific receptor conformations. Biochemical Pharmacology 84 (2), pp. 192-203.
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Eosinophils play a crucial role in the pathogenesis of allergic diseases. Histamine activates eosinophils via the H(4)-receptor (H(4)R). However, pharmacological analysis of the H(4)R in eosinophils is still incomplete, and cell purity is a problem. The H(4)R antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ7777120) has recently been reported to exhibit paradoxical stimulatory effects in some systems. Therefore, the first aim of our study was to pharmacologically re-examine H(x)R subtypes on human eosinophils using a highly purified preparation (97±2%). The second aim was to compare the effects of histamine with those induced by well-known activators of eosinophil functions, i.e. eotaxin-1 and formyl peptides. Histamine and the H(4)R-selective agonist 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine (UR-PI376) increased intracellular calcium concentration ([Ca(2+)](i)) and activated chemotaxis. JNJ7777120 per se exhibited no stimulatory effects but inhibited stimulation by histamine and UR-PI376. Blockade of the H(2)R by famotidine enhanced histamine-induced chemotaxis but not rises in [Ca(2+)](i). Compared to eotaxin and formyl peptides, the effect of histamine on eosinophil chemotaxis was only small. Formyl peptides but not histamine activated reactive oxygen species formation and release of eosinophil peroxidase. In conclusion, histamine is only an incomplete eosinophil activator with the H(2)R blunting the small chemotactic response to H(4)R activation. We also noted several differences in potencies of histamine, UR-PI376 and JNJ7777120 in calcium and chemotaxis assays and when compared to results in the literature. This indicates functional selectivity of H(4)R ligands, thus ligand-specific stabilization of distinct receptor conformations, inducing distinct biological responses.
|Institutions:||Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer)|
|Projects:||GRK 760, Graduiertenkolleg Medizinische Chemie|
|Keywords:||Eosinophils, Histamine H4-receptor, Chemotaxis, Intracellular calcium concentration, Functional selectivity|
|Subjects:||500 Science > 540 Chemistry & allied sciences|
500 Science > 570 Life sciences
600 Technology > 610 Medical sciences Medicine
600 Technology > 615 Pharmacy
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Partially|
|Owner:||Prof. Armin Buschauer|
|Deposited On:||23 Apr 2012 12:51|
|Last Modified:||21 May 2012 21:52|
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