Dataset Information

Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors.

ABSTRACT:

Background and purpose

Functional interactions between the G protein-coupled dopamine D1 and histamine H3 receptors have been described in the brain. In the present study we investigated the existence of D1-H3 receptor heteromers and their biochemical characteristics.

Experimental approach

D1-H3 receptor heteromerization was studied in mammalian transfected cells with Bioluminescence Resonance Energy Transfer and binding assays. Furthermore, signalling through mitogen-activated protein kinase (MAPK) and adenylyl cyclase pathways was studied in co-transfected cells and compared with cells transfected with either D1 or H3 receptors.

Key results

Bioluminescence Resonance Energy Transfer and binding assays confirmed that D1 and H3 receptors can heteromerize. Activation of histamine H3 receptors did not lead to signalling towards the MAPK pathway unless dopamine D1 receptors were co-expressed. Also, dopamine D1 receptors, usually coupled to G(s) proteins and leading to increases in cAMP, did not couple to G(s) but to G(i) in co-transfected cells. Furthermore, signalling via each receptor was blocked not only by a selective antagonist but also by an antagonist of the partner receptor.

Conclusions and implications

D1-H3 receptor heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a G(s)-independent and G(i)-dependent manner. An antagonist of one of the receptor units in the D1-H3 receptor heteromer can induce conformational changes in the other receptor unit and block specific signals originating in the heteromer. This gives rise to unsuspected therapeutic potentials for G protein-coupled receptor antagonists.

SUBMITTER: Ferrada C

PROVIDER: S-EPMC2697789 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Publications

Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors.

Ferrada Carla C Moreno Estefanía E Casadó Vicent V Bongers Gerold G Cortés Antoni A Mallol Josefa J Canela Enric I EI Leurs Rob R Ferré Sergi S Lluís Carme C Franco Rafael R

British journal of pharmacology 20090501 1

<h4>Background and purpose</h4>Functional interactions between the G protein-coupled dopamine D1 and histamine H3 receptors have been described in the brain. In the present study we investigated the existence of D1-H3 receptor heteromers and their biochemical characteristics.<h4>Experimental approach</h4>D1-H3 receptor heteromerization was studied in mammalian transfected cells with Bioluminescence Resonance Energy Transfer and binding assays. Furthermore, signalling through mitogen-activated pr ...[more]

PMID: 19413572

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Project description:Addictive drugs lead to reinforcing properties by increasing dopamine in the nucleus accumbens, which is composed of a core and shell regions. Neurons in the nucleus accumbens are divided into 2 subtypes based on the differential gene expression of the dopamine D₁ receptors and D₂ receptors. In the present study, we investigated the role of D₂ receptors in the nucleus accumbens core in behaviors and signal transduction induced by psychostimulant methamphetamine in mice that were microinjected with adeno-associated virus vectors containing a microRNA (miRNA) sequence for D₂ receptor (adeno-associated virus-miD2r vectors) in the nucleus accumbens core. The adeno-associated virus vectors containing a miRNA sequence for D₂ receptor-treated mice (miD₂r mice) were assessed at a reduction in D₂ receptor, but at no change in dopamine D₁ receptor, in the nucleus accumbens core compared with the adeno-associated virus-Mock vectors-treated mice (Mock mice). miD₂r mice exhibited a reduction in hyperlocomotion that was induced by a single treatment with methamphetamine. The development of locomotor sensitization induced by repeated treatment with methamphetamine exhibited less extension in miD₂r mice. In a place conditioning paradigm, the preferred effects of methamphetamine were significantly weaker in miD₂r mice than in Mock mice. Furthermore, the single treatment with methamphetamine-induced phosphorylation of extracellular signal regulated kinase and cyclic adenosine monophosphate response element-binding protein in the nucleus accumbens core of miD₂r mice was decreased compared with that in Mock mice. Repeated treatment with methamphetamine-induced delta FBJ murine osteosarcoma viral oncogene homolog B accumulation in the nucleus accumbens core of miD₂r mice was also attenuated. These findings suggest that a D₂ receptor-mediated neuronal pathway from the nucleus accumbens core plays an inhibitory role in the development of reinforcing properties.

Dataset Information

Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors.

Similar Datasets

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