title: Dopamine D4 receptor, but not the ADHD-associated D4.7 variant, forms functional heteromers with the dopamine D2S receptor in the brain.
abstract: Polymorphic variants of the dopamine D(4) receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However, the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here, we show that whereas the most frequent 4-repeat (D(4.4)) and the 2-repeat (D(4.2)) variants form functional heteromers with the short isoform of the dopamine D(2) receptor (D(2S)), the 7-repeat risk allele (D(4.7)) does not. D(2) receptor activation in the D(2S)-D(4) receptor heteromer potentiates D(4) receptor-mediated MAPK signaling in transfected cells and in the striatum, which did not occur in cells expressing D(4.7) or in the striatum of knockin mutant mice carrying the 7 repeats of the human D(4.7) in the third intracellular loop of the D(4) receptor. In the striatum, D(4) receptors are localized in corticostriatal glutamatergic terminals, where they selectively modulate glutamatergic neurotransmission by interacting with D(2S) receptors. This interaction shows the same qualitative characteristics than the D(2S)-D(4) receptor heteromer-mediated mitogen-activated protein kinase (MAPK) signaling and D(2S) receptor activation potentiates D(4) receptor-mediated inhibition of striatal glutamate release. It is therefore postulated that dysfunctional D(2S)-D(4.7) heteromers may impair presynaptic dopaminergic control of corticostriatal glutamatergic neurotransmission and explain functional deficits associated with ADHD.
authors.affiliation: Department of Biochemistry and Molecular Biology, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, University of Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: González
authors.forename: C
authors.initials: C
authors.lastname: Rangel-Barajas
authors.forename: M
authors.initials: M
authors.lastname: Peper
authors.forename: R
authors.initials: R
authors.lastname: Lorenzo
authors.forename: E
authors.initials: E
authors.lastname: Moreno
authors.forename: F
authors.initials: F
authors.lastname: Ciruela
authors.forename: J
authors.initials: J
authors.lastname: Borycz
authors.forename: J
authors.initials: J
authors.lastname: Ortiz
authors.forename: C
authors.initials: C
authors.lastname: Lluís
authors.forename: R
authors.initials: R
authors.lastname: Franco
authors.forename: P J
authors.initials: PJ
authors.lastname: McCormick
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
authors.forename: M
authors.initials: M
authors.lastname: Rubinstein
authors.forename: B
authors.initials: B
authors.lastname: Floran
authors.forename: S
authors.initials: S
authors.lastname: Ferré
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D016466:CHO Cells; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D055879:Gene Knock-In Techniques / Q000379:methods; D018698:Glutamic Acid / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D055503:Protein Multimerization; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection / Q000379:methods
chemical_list: D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; D050638:Receptors, Dopamine D4; D018698:Glutamic Acid; D020928:Mitogen-Activated Protein Kinases