Signal transduction mechanism of biased ligands at histamine H2 receptors.

ALONSO NATALIA; MONCZOR FEDERICO; ECHEVERRIA EMILIANA; DAVIO CARLOS; SHAYO CARINA; FERNADEZ NATALIA

BIOCHEMICAL JOURNAL

PORTLAND PRESS LTD

Lugar: Londres; Año: 2014 vol. 459 p. 117 - 126

0264-6021

7TMR exists as conformational collections where different conformations would lead to differential downstream behaviors as receptor phosphorylation, G-protein activation and receptor internalization between others. In this context, a ligand may cause differential activation of some but not all of the signaling events associated to a particular receptor leading to biased agonism. Knowing the importance for research and pharmacological uses of proper ligand classification into agonists, inverse agonists, and antagonists, the aim of the present work was to study the possibility that histamine H2 receptor (H2R) ligands described as inverse agonists due to their negative efficacy at modulating adenylyl cyclase could display some positive efficacy concerning receptor desensitization, internalization or even signaling through an adenylyl cyclase independent pathway. Our present findings indicate that treatment with H2R inverse agonists leads to receptor internalization in HEK293T transfected cells, by a mechanism mediated by arrestin and dynamin but independent of GRK2-mediated phosphorylation. On the other hand we demonstrated that two of the H2R inverse agonists tested, ranitidine and tiotidine, induce also receptor desensitization. Finally, we showed that these ligands are able to display positive efficacy towards ERK1/2 pathway by a mechanism that involves Gβγ and PI3K mediated signaling in both HEK293T transfected cells and in human gastric adenocarcinoma cells. These results point to the pluridimensional aspect of the efficacy of H2R as a phenomenon that could be extended to naïve cells, and challenge previous classification of pharmacologically relevant histaminergic ligands.