title: Dopamine D1-histamine H3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway.
abstract: 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.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 645, 08028 Barcelona, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.forename: Hanne
authors.initials: H
authors.lastname: Hoffmann
authors.forename: Marta
authors.initials: M
authors.lastname: Gonzalez-Sepúlveda
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.forename: Josefa
authors.initials: J
authors.lastname: Mallol
authors.forename: Michel
authors.initials: M
authors.lastname: Vignes
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCormick
authors.forename: Enric I
authors.initials: EI
authors.lastname: Canela
authors.forename: Carme
authors.initials: C
authors.lastname: Lluís
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.forename: Jordi
authors.initials: J
authors.lastname: Ortiz
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006632:Histamine / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017447:Receptors, Dopamine D1; D018100:Receptors, Histamine H3; D006632:Histamine; D048052:Mitogen-Activated Protein Kinase 3; D004298:Dopamine