Evidence against dopamine D1/D2 receptor heteromers
Langue
EN
Article de revue
Ce document a été publié dans
Molecular Psychiatry. 2015-11, vol. 20, n° 11, p. 1373-1385
Résumé en anglais
Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation, because their purported potential to manifest signaling and pharmacological properties that differ from the component receptors ...Lire la suite >
Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation, because their purported potential to manifest signaling and pharmacological properties that differ from the component receptors makes them highly attractive for the development of more selective pharmacological treatments. In particular, dopamine D1 and D2 receptors have been proposed to form hetero-oligomers that couple to Gαq proteins, and SKF83959 has been proposed to act as a biased agonist that selectively engages these receptor complexes to activate Gαq and thus phospholipase C. D1/D2 heteromers have been proposed as relevant to the pathophysiology and treatment of depression and schizophrenia. We used in vitro bioluminescence resonance energy transfer, ex vivo analyses of receptor localization and proximity in brain slices, and behavioral assays in mice to characterize signaling from these putative dimers/oligomers. We were unable to detect Gαq or Gα11 protein coupling to homomers or heteromers of D1 or D2 receptors using a variety of biosensors. SKF83959-induced locomotor and grooming behaviors were eliminated in D1 receptor knockout (KO) mice, verifying a key role for D1-like receptor activation. In contrast, SKF83959-induced motor responses were intact in D2 receptor and Gαq KO mice, as well as in knock-in mice expressing a mutant Ala(286)-CaMKIIα that cannot autophosphorylate to become active. Moreover, we found that, in the shell of the nucleus accumbens, even in neurons in which D1 and D2 receptor promoters are both active, the receptor proteins are segregated and do not form complexes. These data are not compatible with SKF83959 signaling through Gαq or through a D1/D2 heteromer and challenge the existence of such a signaling complex in the adult animals that we used for our studies.< Réduire
Mots clés en anglais
Animals
Corpus Striatum
Dopamine Agonists
Dopamine Antagonists
Grooming
GTP-Binding Protein alpha Subunits
Gq-G11
HEK293 Cells
Humans
Luminescent Proteins
Male
Mice
Inbred C57BL
Knockout
Models
Molecular
Motor Activity
Nucleus Accumbens
Phosphorylation
Protein Multimerization
Protein Structure
Tertiary
Receptors Dopamine D1
Receptors Dopamine D2
Unités de recherche