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 D-1 or D-2 receptors and the histamine H-3 receptor. In addition, we demonstrated two biochemical characteristics of the dopamine D-1 receptor-histamine H-3 receptor heteromer. We have now extended this work to show the dopamine D-1 receptor-histamine H-3 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 D-1 receptors but not in D-1 receptor-deficient mice. On the other hand, the ability of both D-1 and H-3 receptor antagonists to block MAPK activation induced by either D-1 or H-3 receptor agonists was also found in striatal slices. Taken together, these data indicate the occurrence of D-1-H-3 receptor complexes in the striatum and, more importantly, that H-3 receptor agonist-induced ERK 1/2 phosphorylation in striatal slices is mediated by D-1-H-3 receptor heteromers. Moreover, H-3 receptor-mediated phospho-ERK 1/2 labeling co-distributed with D-1 receptor-containing but not with D-2 receptor-containing striatal neurons. These results indicate that D-1-H-3 receptor heteromers work as processors integrating dopamine-and histamine-related signals involved in controlling the function of striatal neurons of the direct striatal pathway.