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

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.