Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases.
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ABSTRACT:
SUBMITTER: De Deurwaerdere P
PROVIDER: S-EPMC8151522 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
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Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases.
De Deurwaerdère Philippe P Chagraoui Abdeslam A
Biomolecules 20210511 5
<i>Biomolecules</i> has launched a Special Issue entitled "Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases [...]. ...[more]
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Project description:During conditions of moderate sodium excess, the dopaminergic system regulates blood pressure and water and electrolyte balance by engendering natriuresis. Dopamine exerts its effects on dopamine receptors, including the dopamine D(3) receptor. G protein-coupled receptor kinase 4 (GRK4), whose gene locus (4p16.3) is linked to essential hypertension, desensitizes the D(1) receptor, another dopamine receptor. This study evaluated the role of GRK4 on D(3) receptor function in human proximal tubule cells. D(3) receptor co-segregated in lipid rafts and co-immunoprecipitated and co-localized in human proximal tubule cells and in proximal and distal tubules and glomeruli of kidneys of Wistar Kyoto rats. Bimolecular fluorescence complementation and confocal microscopy revealed that agonist activation of the receptor initiated the interaction between D(3) receptor and GRK4 at the cell membrane and promoted it intracellularly, presumably en route to endosomal trafficking. Of the four GRK4 splice variants, GRK4-gamma and GRK4-alpha mediated a 3- and 2-fold increase in the phosphorylation of agonist-activated D(3) receptor, respectively. Inhibition of GRK activity with heparin or knockdown of GRK4 expression via RNA interference completely abolished p44/42 phosphorylation and mitogenesis induced by D(3) receptor stimulation. These data demonstrate that GRK4, specifically the GRK4-gamma and GRK4-alpha isoforms, phosphorylates the D(3) receptor and is crucial for its signaling in human proximal tubule cells.
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Project description:The dopamine D3 receptor is a class A, rhodopsin-like G protein-coupled receptor that can form dimers and/or higher order oligomers. However, the molecular basis for production of these complexes is not well defined. Using combinations of molecular modeling, site-directed mutagenesis, and homogenous time-resolved FRET, the interfaces that allow dopamine D3 receptor monomers to interact were defined and used to describe likely quaternary arrangements of the receptor. These were then compared with published crystal structures of dimeric β1-adrenoreceptor, μ-opioid, and CXCR4 receptors. The data indicate important contributions of residues from within each of transmembrane domains I, II, IV, V, VI, and VII as well as the intracellular helix VIII in the formation of D3-D3 receptor interfaces within homo-oligomers and are consistent with the D3 receptor adopting a β1-adrenoreceptor-like quaternary arrangement. Specifically, results suggest that D3 protomers can interact with each other via at least two distinct interfaces: the first one comprising residues from transmembrane domains I and II along with those from helix VIII and a second one involving transmembrane domains IV and V. Moreover, rather than existing only as distinct dimeric species, the results are consistent with the D3 receptor also assuming a quaternary structure in which two transmembrane domain I-II-helix VIII dimers interact to form a "rhombic" tetramer via an interface involving residues from transmembrane domains VI and VII. In addition, the results also provide insights into the potential contribution of molecules of cholesterol to the overall organization and potential stability of the D3 receptor and possibly other GPCR quaternary structures.
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Project description:BACKGROUND:Neuroinflammation constitutes a pathogenic process leading to neurodegeneration in several disorders, including Alzheimer's disease, Parkinson's disease (PD) and sepsis. Despite microglial cells being the central players in neuroinflammation, astrocytes play a key regulatory role in this process. Our previous results indicated that pharmacologic-antagonism or genetic deficiency of dopamine receptor D3 (DRD3) attenuated neuroinflammation and neurodegeneration in two mouse models of PD. Here, we studied how DRD3-signalling affects the dynamic of activation of microglia and astrocyte in the context of systemic inflammation. METHODS:Neuroinflammation was induced by intraperitoneal administration of LPS. The effect of genetic DRD3-deficiency or pharmacologic DRD3-antagonism in the functional phenotype of astrocytes and microglia was determined by immunohistochemistry and flow cytometry at different time-points. RESULTS:Our results show that DRD3 was expressed in astrocytes, but not in microglial cells. DRD3 deficiency resulted in unresponsiveness of astrocytes and in attenuated microglial activation upon systemic inflammation. Furthermore, similar alterations in the functional phenotypes of glial cells were observed by DRD3 antagonism and genetic deficiency of DRD3 upon LPS challenge. Mechanistic analyses show that DRD3 deficiency resulted in exacerbated expression of the anti-inflammatory protein Fizz1 in glial cells both in vitro and in vivo. CONCLUSIONS:These results suggest that DRD3 signalling regulates the dynamic of the acquisition of pro-inflammatory and anti-inflammatory features by astrocytes and microglia, finally favouring microglial activation and promoting neuroinflammation.
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Project description:Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of the addiction can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. YQA14 is a novel D3R antagonist that has exhibited pharmacotherapeutic efficacy in reducing cocaine and amphetamine reward and relapse to drug seeking in mice. In this study we investigated the effects of YQA14 on morphine-induced context-specific locomotor sensitization in mice. We showed that repeated injection of YQA14 (6.25-25?mg/kg every day ip) prior to morphine (10?mg/kg every day sc) not only inhibited the acquisition, but also significantly attenuated the expression of morphine-induced locomotor sensitization. Furthermore, in the expression phase, one single injection of YQA14 (6.25-25?mg/kg, ip) dose-dependently inhibited the expression of morphine-induced behavioral sensitization. Moreover, YQA14 inhibited the expression of morphine-induced behavioral sensitization in wild mice (WT), but not in D3R knockout (D3R-/-) mice in the expression phase. In addition, D3R-/- mice also displayed the reduction in the expression phase compared with WT mice. In summary, this study demonstrates that blockade or knockout of the D3R inhibits morphine-induced behavior sensitization, suggesting that D3R plays an important role in the pathogenesis and etiology of morphine addiction, and it might be a potential target for clinical management of opioid addiction.
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Project description:D3 dopamine receptor (D3R)-deficient mice have renin-dependent hypertension associated with sodium retention, but the hypertension is mild. To determine whether any compensatory mechanisms in the kidney are involved in the regulation of blood pressure with disruption of Drd3, we measured the renal protein expression of all dopamine receptor subtypes (D1R, D2R, D4R, and D5R) in D3R homozygous (D3(-/-)) and heterozygous (D3(+/-)) knockout mice and their wild-type (D3(+/+)) littermates. The renal immunohistochemistry and protein expression of D5R were increased (n=5/group) in D3(-/-) mice; renal D4R protein expression was decreased, whereas renal protein expressions of D1R and D2R were similar in both groups. Renal D5R protein expression was also increased in D3(+/-) (n=5/group) relative to D3(+/+) mice, whereas D1R, D2R, and D4R protein expressions were similar in D3(+/-) and D3(+/+) mice. The increase in renal D5R protein expression was abolished when D3(-/-) mice were fed a high-salt diet. Treatment with the D1-like receptor antagonist, SCH23390, increased the blood pressure in anesthetized D3(-/-) but not D3(+/+) mice (n=4/group), suggesting that the renal upregulation of D5R may have minimized the hypertension in D3(-/-) mice. The renal D5R protein upregulation was not caused by increased transcription because renal mRNA expression of D5R was similar in D3(-/-) and D3(+/+) mice. Our findings suggest that the renal upregulation of D5R may have minimized the hypertension that developed in D3(-/-) mice.
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Project description:The dopamine D3 receptor, which is highly enriched in nucleus accumbens (NAc), has been suggested to play an important role in reinforcement and reward. To understand the potential cellular mechanism underlying D3 receptor functions, we examined the effect of D3 receptor activation on GABAA receptor (GABAAR)-mediated current and inhibitory synaptic transmission in medium spiny neurons of NAc. Application of PD128907 [(4aR,10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a specific D3 receptor agonist, caused a significant reduction of GABAAR current in acutely dissociated NAc neurons and miniature IPSC amplitude in NAc slices. This effect was blocked by dialysis with a dynamin inhibitory peptide, which prevents the clathrin/activator protein 2 (AP2)-mediated GABAA receptor endocytosis. In addition, the D3 effect on GABAAR current was prevented by agents that manipulate protein kinase A (PKA) activity. Infusion of a peptide derived from GABAAR beta subunits, which contains an atypical binding motif for the clathrin AP2 adaptor complex and the major PKA phosphorylation sites and binds with high affinity to AP2 only when dephosphorylated, diminished the D3 regulation of IPSC amplitude. The phosphorylated equivalent of the peptide was without effect. Moreover, PD128907 increased GABAAR internalization and reduced the surface expression of GABAA receptor beta subunits in NAc slices, which was prevented by dynamin inhibitory peptide or cAMP treatment. Together, our results suggest that D3 receptor activation suppresses the efficacy of inhibitory synaptic transmission in NAc by increasing the phospho-dependent endocytosis of GABAA receptors.
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Project description:Hyperammonemia is frequently seen in tumor microenvironments as well as in liver diseases where it can lead to severe brain damage or death. Ammonia induces autophagy, a mechanism that tumor cells may use to protect themselves from external stresses. However, how cells sense ammonia has been unclear. Here we show that culture medium alone containing Glutamine can generate milimolar of ammonia at 37 degrees in the absence of cells. In addition, we reveal that ammonia acts through the G protein-coupled receptor DRD3 (Dopamine receptor D3) to induce autophagy. At the same time, ammonia induces DRD3 degradation, which involves PIK3C3/VPS34-dependent pathways. Ammonia inhibits MTOR (mechanistic target of Rapamycin) activity and localization in cells, which is mediated by DRD3. Therefore, ammonia has dual roles in autophagy: one to induce autophagy through DRD3 and MTOR, the other to increase autophagosomal pH to inhibit autophagic flux. Our study not only adds a new sensing and output pathway for DRD3 that bridges ammonia sensing and autophagy induction, but also provides potential mechanisms for the clinical consequences of hyperammonemia in brain damage, neurodegenerative diseases and tumors.
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Project description:The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation of neuronal development, in promoting structural plasticity and in triggering key intracellular events with neuroprotective potential. A new role for D3R-dependent neurotransmission has thus been proposed both in preserving DA neuron homeostasis in physiological conditions and in preventing pathological alterations that may lead to neurodegeneration. Interestingly, there is evidence that nicotinic acetylcholine receptors (nAChR) located on DA neurons also provide neurotrophic support to DA neurons, an effect requiring functional D3R and suggesting the existence of a positive cross-talk between these receptor systems. Increasing evidence suggests that, as with the majority of G protein-coupled receptors (GPCR), the D3R directly interacts with other receptors to form new receptor heteromers with unique functional and pharmacological properties. Among them, we recently identified a receptor heteromer containing the nAChR and the D3R as the molecular effector of nicotine-mediated neurotrophic effects. This review summarizes the functional and pharmacological characteristics of D3R, including the capability to form active heteromers as pharmacological targets for specific neurodegenerative disorders. In particular, the molecular and functional features of the D3R-nAChR heteromer will be especially discussed since it may represent a possible key etiologic effector for DA-related pathologies, such as Parkinson's disease (PD), and a target for drug design.
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Project description:The dopamine D3 receptor (DRD3) gene has been implicated in schizophrenia, autism, and substance use-disorders and is related to emotion reactivity, executive functioning, and stress-responding, processes impaired in posttraumatic stress disorder (PTSD). The aim of this candidate gene study was to evaluate DRD3 polymorphisms for association with PTSD. The discovery sample was trauma-exposed White, non-Hispanic U.S. veterans and their trauma-exposed intimate partners (N = 491); 60.3% met criteria for lifetime PTSD. The replication sample was 601 trauma-exposed African American participants living in Detroit, Michigan; 23.6% met criteria for lifetime PTSD. Genotyping was based on high-density bead chips. In the discovery sample, 4 single nucleotide polymorphisms (SNPs), rs2134655, rs201252087, rs4646996, and rs9868039, showed evidence of association with PTSD and withstood correction for multiple testing. The minor alleles were associated with reduced risk for PTSD (OR range = 0.59 to 0.69). In the replication sample, rs2251177, located 149 base pairs away from the most significant SNP in the discovery sample, was nominally associated with PTSD in men (OR = 0.32). Although the precise role of the D3 receptor in PTSD is not yet known, its role in executive functioning and emotional reactivity, and the sensitivity of the dopamine system to environmental stressors could potentially explain this association.
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Project description:Previous reports have identified greater sensitivity to the locomotor-stimulating, sensitizing, and reinforcing effects of amphetamine in inbred C57BL/6J mice relative to inbred DBA/2J mice. The dopamine D3 receptor (D3R) plays an inhibitory role in the regulation of rodent locomotor activity, and exerts inhibitory opposition to D1 receptor (D1R)-mediated signaling. Based on these observations, we investigated D3R expression and D3R-mediated locomotor-inhibitory function, as well as D1R binding and D1R-mediated locomotor-stimulating function, in C57BL/6J and DBA/2J mice. C57BL/6J mice exhibited lower D3R binding density (-32%) in the ventral striatum (nucleus accumbens/islands of Calleja), lower D3R mRNA expression (-26%) in the substantia nigra/ventral tegmentum, and greater D3R mRNA expression (+40%) in the hippocampus, relative to DBA/2J mice. There were no strain differences in DR3 mRNA expression in the ventral striatum or prefrontal cortex, nor were there differences in D1R binding in the ventral striatum. Behaviorally, C57BL/6J mice were less sensitive to the locomotor-inhibitory effect of the D3R agonist PD128907 (10 microg/kg), and more sensitive to the locomotor-stimulating effects of novelty, amphetamine (1 mg/kg), and the D1R-like agonist +/- -1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8,-diol hydrochloride (SKF38393) (5-20 mg/kg) than DBA/2J mice. While the selective D3R antagonist N-(4-[4-{2,3-dichlorphenyl}-1 piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904) (0.01-1.0 mg/kg) augmented novelty-, amphetamine-, and SKF38393-induced locomotor activity in DBA/2J mice, it reduced novelty-induced locomotor activity in C57BL/6J mice. Collectively, these results demonstrate that C57BL/6J mice exhibit less D3R-mediated inhibitory function relative to DBA/2J mice, and suggest that reduced D3R-mediated inhibitory function may contribute to heightened sensitivity to the locomotor-stimulating effects of amphetamine in the C57BL/6J mouse strain. Furthermore, these data demonstrate that comparisons between C57BL/6J and DBA/2J mouse strains provide a model for elucidating the molecular determinants of genetic influence on D3R function.
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