PT  - JOURNAL ARTICLE
AU  - Natalia Alonso
AU  - Natalia Fernandez
AU  - Cintia Notcovich
AU  - Federico Monczor
AU  - May Simaan
AU  - Alberto Baldi
AU  - Jorge Silvio Gutkind
AU  - Carlos Davio
AU  - Carina Shayo
TI  - Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration
AID  - 10.1124/mol.112.083394
DP  - 2013 Mar 05
TA  - Molecular Pharmacology
PG  - mol.112.083394
4099  - http://molpharm.aspetjournals.org/content/early/2013/03/05/mol.112.083394.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/03/05/mol.112.083394.full
AB  - G-protein coupled receptor (GPCR) signaling does not result from sequential activation of a linear pathway of proteins/enzymes, but rather from complex interactions of multiple, branched signaling routes, 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 demonstrated the existence of a cross-desensitization between both receptors independent of protein kinase A (PKA) or C (PKC). H1R agonist stimulation inhibited cell proliferation and induced apoptosis in U937 cells following treatment for 48h. H1R-induced antiproliferative and apoptotic response was inhibited by an H2R agonist suggesting that the crosstalk between both receptors modifies their function. Binding and confocal microscopy studies revealed cointernalization of both receptors upon treatment with the agonists. In order to evaluate potential heterodimerization of the receptors, sensitized emission FRET experiments were performed in HEK293T cells using H1R-CFP and H2R-YFP. To our knowledge these findings may represent the first demonstration of agonist-induced heterodimerization of the H1R and H2R. In addition, we also show that the inhibition of the internalization process did not prevent receptor cross-desensitization which was mediated by GRK2. Our study provides new insights into the complex signaling network mediated by histamine and further knowledge for the rational use of its ligands.