Dopamine D1-histamine H3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway

Estefanía Moreno, Hanne Hoffmann, Marta Gonzalez-Sepúlveda, Gemma Navarro, Vicent Casadó, Antoni Cortés, Josefa Mallol, Michel Vignes, Peter J. McCormick, Enric I. Canela, Carme Lluís, Rosario Moratalla, Sergi Ferré, Jordi Ortiz, Rafael Franco*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

100 Citations (Scopus)


Previously, using artificial cell systems, we identified receptor heteromers between the dopamine D1 or D2 receptors and the 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 D 1 receptor-histamine H3 receptor heteromer exists in the brain and serves to provide a novel link between the MAPK pathway and the GABAergic neurons in the direct striatal efferent pathway. Using the biochemical characteristics identified previously, we found that the ability of H 3 receptor activation to stimulate p44 and p42 extracellular signal-regulated MAPK (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 D 1-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 D 1-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.

Original languageAmerican English
Pages (from-to)5846-5854
Number of pages9
JournalJournal of Biological Chemistry
Issue number7
Publication statusPublished - 18 Feb 2011


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