Histamine H2 receptor overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate cAMP signaling

MONCZOR F; FERNÁNDEZ N; RIVEIRO E; MLADOVAN A; BALDI A; SHAYO C; DAVIO C

BIOCHEMICAL PHARMACOLOGY

Elsevier Science Inc

Año: 2006 vol. 14 p. 1219 - 1228

0006-2952

Knowing that cell-surface receptors that recognize and respond to extracellular stimuli arekey components for the regular communication between individual cells required for thesurvival of any living organism, the aim of the present work was to investigate the effect ofH2R overexpression on the U937 signal transduction pathway and its consequences on cellproliferation and differentiation. The overexpression ofH2R led to an increase in cAMP basallevels, a leftward shift of agonist concentration–response curves, and similar maximalresponse to agonist treatment, suggesting that overexpressed H2Rs act as functional sparereceptors. In this system cells triggered several mechanisms tending to restore cAMP basallevels to those of the naı¨ve cells. H2R overexpression induced PDE activity stimulation andGRK2 overexpression. In spite of the onset of these regulatory mechanisms, H2 agonist androlipram treatments induced the terminal differentiation of the H2R overexpressed clone,conversely to the naı¨ve cells. Present findings show that stably H2R overexpression alterscAMP signalling as the result of not only the amounts of second messenger generated butalso the activation or upregulation of various components of signalling cascade, leading toan adapted biologically unique system. This adaptation may represent an advantage or adisadvantage, depending on the biological system, but in any case, the existence ofcompensatory mechanisms should be considered when a clinical treatment is designed.