IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Cointernalization of H1 and H2 histamine receptors reveals new insight into histamine signal integration.
Autor/es:
NATALIA ALONSO; NATALIA FERNANDEZ; CINTIA NOTCOVICH, ; FEDERICO MONCZOR, ; ALBERTO BALDI, .; SILVIO GUTKIND, ; CARLOS DAVIO, ; CARINA SHAYO
Lugar:
sAN CARLOS DE bARILOCHE
Reunión:
Simposio; The Second South American Spring Symposium in Signal Trasduction and Molecular Medicine; 2012
Resumen:
GPCR signaling does not result from sequential activation of a linear pathway of proteins/enzymes, but rather results from the complex interactions of multiple, branched signaling pathways, ie, signaling networks. In this work we present an exhaustive study of the crosstalk between H1 and H2 histamine receptors (H1R and H2R) in U937 cells and CHO transfected cells. By desensitization assays we could demonstrate that there is a cross-desensitization between both receptors independent of the second messenger kinases proteins, PKA or PKC. Our results showed that H1R agonist inhibits cell proliferation and induces apoptosis in U937 cells after 48 h of treatment. This antiproliferative and apoptotic effect was blocked by the presence of the H2R agonist, demonstrating that the crosstalk between these two receptors alters their signaling. Binding studies and confocal microscopy revealed cointernalization of the receptors upon both agonist treatments. In order to determine the potential heterodimerization of the receptors, sensitized emission FRET experiments were performed in HEK293T cells using H1R-CFP and H2R-YFP. Our results determined for the first time the agonist-induced heterodimerization of the H1R and H2R. This work provides new evidence on the mechanism of the cross-regulation between H1R and H2R and its pathophysiological role. The new knowledge presented contributes to the compression of the complex signaling network of histamine contributing to a rational use of their ligands.