title: Cross-desensitization and cointernalization of H1 and H2 histamine receptors reveal new insights into histamine signal integration.
abstract: 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. H1R-agonist stimulation inhibited cell proliferation and induced apoptosis in U937 cells following treatment of 48 hours. H1R-induced 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 agonist-induced 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.
authors: Laboratorio de Farmacología y Patología Molecular, Instituto de Biología y Medicina Experimental, Buenos Aires, Argentina.
authors: Natalia
authors: N
authors: Alonso
authors: Natalia
authors: N
authors: Fernandez
authors: Cintia
authors: C
authors: Notcovich
authors: Federico
authors: F
authors: Monczor
authors: May
authors: M
authors: Simaan
authors: Alberto
authors: A
authors: Baldi
authors: J Silvio
authors: JS
authors: Gutkind
authors: Carlos
authors: C
authors: Davio
authors: Carina
authors: C
authors: Shayo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D057809:HEK293 Cells; D006632:Histamine / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D015398:Signal Transduction; D020298:U937 Cells
chemical_list: D017442:Histamine Agonists; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D006632:Histamine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D054769:G-Protein-Coupled Receptor Kinase 2