INVESTIGADORES
MONCZOR Federico
artículos
Título:
Physiological implications of biased signaling at histamine H2 receptors.
Autor/es:
ALONSO NATALIA; ZAPPIA, CARLOS DANIEL; CABRERA, MAIA; DAVIO CARLOS; SHAYO CARINA; MONCZOR FEDERICO; FERNANDEZ NATALIA
Revista:
Frontiers in Pharmacology
Editorial:
Frontiers Editorial Office
Referencias:
Lugar: Lausanne; Año: 2015 vol. 6
Resumen:
Histamine mediates numerous functions acting through its four receptor
subtypes all belonging to the large family of seven transmembrane
G-protein coupled receptors. In particular, histamine H2 receptor (H2R)
is mainly involved in gastric acid production, becoming a classic
pharmacological target to treat Zollinger-Ellison disease and gastric
and duodenal ulcers. H2 ligands rank among the most widely prescribed
and over the counter-sold drugs in the world. Recent evidence indicate
that some H2R ligands display biased agonism, selecting and triggering
some, but not all, of the signaling pathways associated to the H2R. The
aim of the present work is to study whether famotidine, clinically
widespread used ligand acting at H2R, exerts biased signaling. Our
findings indicate that while famotidine acts as inverse agonist
diminishing cAMP basal levels, it mimics the effects of histamine and
the agonist amthamine concerning receptor desensitization and
internalization. Moreover, the treatment of HEK293T transfected cells
with any of the three ligands lead to a concentration dependent pERK
increment. Similarly in AGS gastric epithelial cells, famotidine
treatment led to both, the reduction in cAMP levels as well as the
increment in ERK phosphorylation, suggesting that this behavior could
have pharmacological relevant implications. Based on that, histidine
decarboxylase expression was studied by quantitative PCR in AGS cells
and its levels were increased by famotidine as well as by histamine and
amthamine. In all cases, the positive regulation was impeded by the MEK
inhibitor PD98059, indicating that biased signaling toward ERK1/2
pathway is the responsible of such enzyme regulation. These results
support that ligand bias is not only a pharmacological curiosity but has
physiological and pharmacological implications on cell metabolism.