Dopamine D-histamine H 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

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107 Citations (Scopus)


Previously, using artificial cell systems, we identified receptor heteromers between the dopamine D or D receptors and the histamine H receptor. In addition, we demonstrated two biochemical characteristics of the dopamine D receptor-histamine H receptor heteromer. We have now extended this work to show the dopamine D receptor-histamine H 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 receptor activation to stimulate p44 and p42 extracellular signal-regulated MAPK (ERK 1/2) phosphorylation was only observed in striatal slices of mice expressing D receptors but not in D receptor-deficient mice. On the other hand, the ability of both D and H receptor antagonists to block MAPK activation induced by either D or H receptor agonists was also found in striatal slices. Taken together, these data indicate the occurrence of D -H receptor complexes in the striatum and, more importantly, that H receptor agonist-induced ERK 1/2 phosphorylation in striatal slices is mediated by D-H receptor heteromers. Moreover, H receptor-mediated phospho-ERK 1/2 labeling co-distributed with D receptor-containing but not with D receptor-containing striatal neurons. These results indicate that D -H 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 languageEnglish
Pages (from-to)5846-5854
Number of pages9
JournalJournal of Biological Chemistry
Issue number7
Publication statusPublished - 18 Feb 2011

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