Signal transduction mechanism of biased ligands at histamine H2 receptors.

ALONSO N; MONCZOR F; ECHEVERRIA E; DAVIO C; SHAYO C; FERNANDEZ N

BIOCHEMICAL JOURNAL

PORTLAND PRESS LTD

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

0264-6021

7TMR exists as conformational collections in which different conformations would lead to differential downstream behaviors such as receptor phosphorylation, G-protein activation and receptor internalization among others. In this context, a ligand may cause differential activation of some, but not all, of the signaling events, which are associated to a particular receptor, and it would lead to biased agonism. The aim of the present work is to study if histamine H2 receptor (H2R) ligands -described as inverse agonists because of 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 being independent of GRK2-mediated phosphorylation. On the other hand we prove that two of the H2R inverse agonists tested, ranitidine and tiotidine, also induce receptor desensitization. Finally, we show 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 human gastric adenocarcinoma cells. These results point to the aspect of pluridimensional efficacy of H2R as a phenomenon that could be extended to naïve cells, and challenge previous classification of pharmacologically relevant histaminergic ligands.