INVESTIGADORES
DAVIO Carlos Alberto
artículos
Título:
Cross-desensitization and cointernalization of H1 and H2 histamine receptors reveal new insights into histamine signal integration.
Autor/es:
ALONSO NATALIA; FERNADEZ NATALIA; NOTCOVICH CINTIA; MONCZOR FEDERICO; SIMAAN M; BALDI ALBERTO; GUTKIND JS; DAVIO CARLOS; SHAYO CARINA
Revista:
MOLECULAR PHARMACOLOGY
Editorial:
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Referencias:
Lugar: Baltimore; Año: 2013 vol. 83 p. 1087 - 1098
ISSN:
0026-895X
Resumen:
G protein-coupled receptor signaling does not result from
sequential activation of a linear pathway of proteins/enzymes,
but rather from complex interactions of multiple, branched
signaling routes, i.e., signaling networks. In this work we present
an exhaustive study of the cross-talk between H1 and H2
histamine receptors (H1R and H2R) in U937 cells and Chinese
hamster ovary-transfected cells. By desensitization assays we
demonstrated the existence of a crossdesensitization between
both receptors independent of protein kinase A or C. H1Ragonist
stimulation inhibited cell proliferation and induced
apoptosis in U937 cells following treatment of 48 hours. H1Rinduced
antiproliferative and apoptotic response was inhibited
by an H2R agonist suggesting that the cross-talk between
both receptors modifies their function. Binding and confocal
microscopy studies revealed cointernalization of both receptors
upon treatment with the agonists. To evaluate potential heterodimerization
of the receptors, sensitized emission fluorescence
resonance energy transfer experiments were performed in
human embryonic kidney 293T cells using H1R-cyan fluorescent
protein and H2R-yellow fluorescent protein. To our knowledge
these findings may represent the first demonstration of agonistinduced
heterodimerization of the H1R and H2R. In addition,
we also show that the inhibition of the internalization process
did not prevent receptor crossdesensitization, which was
mediated by G protein-coupled receptor kinase 2. Our study
provides new insights into the complex signaling network
mediated by histamine and further knowledge for the rational
use of its ligands.