Histamine augments β2-adrenoceptor-induced cyclic AMP accumulation in human prostate cancer cells DU-145 independently of known histamine receptors

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Abstract

Androgen-independent prostate cancer cells DU-145 express a number of G protein-coupled receptors, including histamine H1 receptors. There is evidence for the presence of β-adrenoceptors in the human prostate, and in this work we set out to characterise the expression of β-adrenoceptors by DU-145 cells, their linking to cyclic AMP (cAMP) formation and the possible modulation by histamine H1 receptors of β-adrenoceptor function. Saturation [3H]-dihydroalprenolol binding indicated that DU-145 cells express moderate levels of β-adrenoceptors (22.7 ± 2.5 fmol/mg protein), which belong to the β2-subtype as assessed by inhibition by the antagonists ICI-118,551 and CGP-20712A. Inhibition of [3H]-dihydroalprenolol binding by agonists (noradrenaline, adrenaline and isoproterenol) showed the presence of both high-(53-59%) and low-affinity binding sites. β-Adrenoceptor stimulation with isoproterenol resulted in robust [3H]-cAMP accumulation (10-30-fold of basal, EC50 142 nM; pEC50 6.85 ± 0.05). While not having effect of its own on basal [3H]-cAMP accumulation, histamine significantly augmented the β2-adrenoceptor-induced response (overall effect 152 ± 6% of isoproterenol alone) with EC50 1.35 μM (pEC50 5.87 ± 0.06). This effect was independent of extracellular Ca2+, insensitive to antagonists/agonists at H1, H2 or H3/H4 receptors and mimicked by drugs containing an imidazole ring in their chemical structure and by imidazole itself. Taken together, our results show that in DU-145 cells histamine augments β2-adrenoceptor-induced cAMP independently of the activation of known histamine receptors. The effect may involve other mechanisms such as allosteric modulation of β2-adrenoceptors by the imidazole moiety of histamine.

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