Histamine augments beta2-adrenoceptor-induced cyclic AMP accumulation in human prostate cancer cells DU-145 independently of known histamine receptors.
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.
Ramos-Jiménez
Judith
J
Departamento de Fisiología, Biofísica y Neurociencias, Cinvestav, México, D.F., Mexico; Sección Externa de Farmacología, Cinvestav, México, D.F., Mexico.
Soria-Jasso
Luis-Enrique
LE
López-Colombo
Aurelio
A
Reyes-Esparza
Jorge-Alberto
JA
Camacho
Javier
J
Arias-Montaño
José-Antonio
JA
D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D004082:Dihydroalprenolol / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D011968:Receptors, Histamine / Q000502:physiology*; D015032:Zinc / Q000494:pharmacology
D018343:Receptors, Adrenergic, beta-2; D011968:Receptors, Histamine; D004082:Dihydroalprenolol; D006632:Histamine; D000242:Cyclic AMP; D015032:Zinc; D007545:Isoproterenol