Histamine augments beta2-adrenoceptor-induced cyclic AMP accumulation in human prostate cancer cells DU-145 independently of known histamine receptors

Biochem Pharmacol. 2007 Mar 15;73(6):814-23. doi: 10.1016/j.bcp.2006.11.022. Epub 2006 Dec 1.


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 beta-adrenoceptors in the human prostate, and in this work we set out to characterise the expression of beta-adrenoceptors by DU-145 cells, their linking to cyclic AMP (cAMP) formation and the possible modulation by histamine H1 receptors of beta-adrenoceptor function. Saturation [3H]-dihydroalprenolol binding indicated that DU-145 cells express moderate levels of beta-adrenoceptors (22.7+/-2.5 fmol/mg protein), which belong to the beta2-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. beta-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 beta2-adrenoceptor-induced response (overall effect 152+/-6% of isoproterenol alone) with EC50 1.35 microM (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 beta2-adrenoceptor-induced cAMP independently of the activation of known histamine receptors. The effect may involve other mechanisms such as allosteric modulation of beta2-adrenoceptors by the imidazole moiety of histamine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cyclic AMP / metabolism*
  • Dihydroalprenolol / metabolism
  • Histamine / pharmacology*
  • Humans
  • Isoproterenol / pharmacology
  • Male
  • Prostatic Neoplasms / metabolism*
  • Receptors, Adrenergic, beta-2 / physiology*
  • Receptors, Histamine / physiology*
  • Zinc / pharmacology


  • Receptors, Adrenergic, beta-2
  • Receptors, Histamine
  • Dihydroalprenolol
  • Histamine
  • Cyclic AMP
  • Zinc
  • Isoproterenol