TY - JOUR T1 - Functional histamine H<sub>3</sub> and adenosine A<sub>2A</sub> receptor heteromers in recombinant cells and rat striatum JF - bioRxiv DO - 10.1101/171736 SP - 171736 AU - Ricardo Márquez-Gómez AU - Citlaly Gutiérrez-Rodelo AU - Meridith T. Robins AU - Juan-Manuel Arias AU - Jesús-Alberto Olivares-Reyes AU - Richard M. van Rijn AU - José-Antonio Arias-Montaño Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/08/02/171736.abstract N2 - In the striatum, histamine H3 receptors (H3Rs) are co-expressed with adenosine A2A receptors (A2ARs) in the cortico-striatal glutamatergic afferents and the GABAergic medium-sized spiny neurons that originate the indirect pathway of the basal ganglia. This location allows H3Rs and A2ARs to regulate the striatal GABAergic and glutamatergic transmission. However, whether these receptors interact to modulate the intra-striatal synaptic transmission has not yet been assessed. To test this hypothesis a heteromer-selective in vitro assay was used to detect functional complementation between a chimeric A2AR302-Gαqi4 and wild-type H3Rs in transfected HEK-293 cells. H3R activation with the agonist RAMH resulted in Ca2+ mobilization (pEC50 7.31 ± 0.23; maximal stimulation, Emax 449 ± 25 % of basal) indicative of receptor heterodimerization. This response was not observed with histamine, suggesting a RAMH bias for heteromers. Functional A2AR-H3R heteromers were confirmed by co-immunoprecipitation and observations of differential cAMP signaling when both receptors were co-expressed in the same cell. In membranes from rat striatal synaptosomes, H3R activation decreased A2AR affinity for the agonist CGS-21680 (pKi values 8.10 ± 0.04 and 7.70 ± 0.04). Moreover, H3Rs and A2ARs co-immunoprecipitated in protein extracts from striatal synaptosomes. These results support the existence of a H3R/A2AR heteromer, and reveal a new mechanism by which these receptors may modulate the unction of the striatum and the basal ganglia. ER -