ENHANCEMENT OF BETA-ADRENERGIC-INDUCED CAMP ACCUMULATION IN ACTIVATEDT-CELLS

Agonist stimulation of the beta-adrenergic receptor on T-cells results in the production of cAMP, which has been correlated with modulation of T-cell function. In previous studies, we have demonstrated that the mitogen PHA can synergistically enhance the accumulation of cAMP in T -cells in response to the agonist isoproterenol. In this report we hav e investigated the mechanisms by which dual stimulation of T-cells act s to synergistically enhance cAMP accumulation. The results demonstrat e that increasing the levels of intracellular calcium with ionomycin o r thapsigargin enhanced isoproterenol-induced cAMP accumulation in T-c ells. In contrast, PHA enhanced isoptoterenol-induced cAMP by a calciu m-independent mechanism as evidenced by stimulation with isoproterenol plus PHA in calcium-free medium. Further studies revealed that PHA pr evented both sequestration of the beta-adrenergic receptor and its dis sociation from Gs protein in response to isoproterenol stimulation. In contrast, PHA did not prevent the functional uncoupling of the beta-a drenergic receptor from adenylyl cyclase, suggesting that additional m echanisms are likely involved. In summary, these studies demonstrate t hat dual receptor signalling of T-cells increases cAMP accumulation an d offers a potential mechanism for catecholamine modulation of T-cell function. (C) 1994 Wiley-Liss, Inc.