Home Current Issue Papers in Press Editors' Picks Minireviews Institution: Biblioteca de la Universitat de Barcelona Dopamine D1-histamine H3 receptor heteromers provide a selective link to the map-kinase signalling in gabaergic neurons of the direct striatal pathway Estefania Moreno1, Hanne Hoffman2, Marta Gonzalez-Sepulveda3, Gemma Navarro1, Vicent Casado1, Antoni Cortes1, Josefa Mallol1, Michel Vignes4, Peter J. McCormick1, Enric I. Canela1, Carme Lluis1, Rosario Moratalla5, Sergi Ferre6, Jordi Ortiz3 and Rafael Franco7,* 1 University of Barcelona, Spain; 2 Universitat Autonoma de Barcelona., Spain; 3 Universitat Autonoma de Barcelona, Spain; 4 CNRS, University of Montpellier, France; 5 Instituto Cajal, Consejo Superior de Investigaciones Cientificas, Spain; 6 National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, United States; 7 Institute for Biomedical Research August Pi i Sunyer, Spain * Corresponding author; email: rfranco{at}unav.es Abstract Previously, using artificial cell systems, we identified receptor heteromers between the dopamine D1 or D2 receptors and histamine H3 receptor. In addition we demonstrated two biochemical characteristics of the dopamine D1 receptor-histamine H3 receptor heteromer. We have now extended this work to show the dopamine D1 receptor-histamine H3 receptor heteromer exists in the brain and serves to provide a novel link between the Mitogen Activated Protein Kinase (MAPK) pathway and the GABAergic neurons in the direct striatal efferent pathway. Using the biochemical characteristics identified previously we found that the ability of H3 receptor activation to stimulate p44 and p42 extracellular signal-regulated MAP Kinase (ERK 1/2) phosphorylation was only observed in striatal slices of mice expressing D1 receptors but not in D1-receptor-deficient mice. On the other hand, the ability of both D1 and H3 receptor antagonists to block MAPK activation induced by either D1 or H3 receptor agonists was also found in striatal slices. Taken together these data indicate the occurrence of D1-H3 receptor complexes in the striatum and, more importantly, that H3 receptor agonist-induced ERK 1/2 phosphorylation in striatal slices is mediated by D1-H3 receptor heteromers. Moreover, H3 receptor-mediated phospho-ERK 1/2 labeling co-distributed with D1-receptor-containing but not with D2-receptor-containing striatal neurons. These results indicate that D1-H3 receptor heteromers work as processors integrating dopamine- and histamine-related signals involved in controlling the function of striatal neurons of the direct striatal pathway.