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Nature Communications Jun 2022Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological...
Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207. The structure reveals unusual binding of two fenoldopam molecules, one to the orthosteric binding pocket (OBP) and the other to the extended binding pocket (EBP). In contrast, one elongated tavapadon molecule binds to D1R, extending from OBP to EBP. Moreover, LY3154207 stabilizes the second intracellular loop of D1R in an alpha helical conformation to efficiently engage the G protein. Through a combination of biochemical, biophysical and cellular assays, we further show that the broad conformation stabilized by two fenoldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R.
Topics: Cryoelectron Microscopy; Dopamine; Dopamine Agonists; Fenoldopam; Ligands; Receptors, Dopamine D1
PubMed: 35676276
DOI: 10.1038/s41467-022-30929-w -
European Journal of Pharmacology Dec 2023Dopamine receptors can form heteromeric interactions with other receptors, including glutamate receptors, and present a novel pharmacological target because it...
Dopamine receptors can form heteromeric interactions with other receptors, including glutamate receptors, and present a novel pharmacological target because it contribute to dopamine-dysregulated brain disorders such as addiction and other motor-related diseases. In addition, dopamine receptors D2 (D2Rs) and glutamate NMDA receptors subtype-NR2B have been implicated in morphine use disorders; however, the molecular mechanism underlying the heteromeric complex of these two receptors in morphine use disorders is unclear. Herein, we focus on interactions between D2R and NR2B in morphine-induced conditioned place preference (CPP) and hyperlocomotion mice models. We found that the D2R-NR2B complex significantly increases in morphine-induced mice models, accompanied by ERK signaling impairment, implying the complex could contribute to the morphine addiction pathophysiological process. Further, we design a brain-penetrant interfering peptide (TAT-D2-KT), which could disrupt interactions of D2R-NR2B and decrease addictive-like behaviors concurrent to ERK signaling improvement. In summary, our data provided the first evidence for a D2R-NMDAR complex formation in morphine use disorders and its underlying mechanism of ERK signaling, which could present a novel therapeutic target with direct implications for morphine acquisition and relapse treatment.
Topics: Mice; Animals; Morphine; Receptors, Dopamine D2; Conditioning, Classical; Brain; Morphine Dependence; Receptors, N-Methyl-D-Aspartate; Receptors, Dopamine D1
PubMed: 37939993
DOI: 10.1016/j.ejphar.2023.176174 -
Pharmacological Research Nov 2020Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely... (Review)
Review
Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely linked to neurological disorders such as schizophrenia, Parkinson's disease, depression, attention deficit-hyperactivity, and restless leg syndrome. Unfortunately, several dopamine receptor-based agonists used to treat some of these diseases cause nausea and vomiting as impending side-effects. The high degree of cross interactions of dopamine receptor ligands with many other targets including G-protein coupled receptors, transporters, enzymes, and ion-channels, add to the complexity of discovering new targets for the treatment of nausea and vomiting. Using activation status of signaling cascades as mechanism-based biomarkers to foresee drug sensitivity combined with the development of dopamine receptor-based biased agonists may hold great promise and seems as the next step in drug development for the treatment of such multifactorial diseases. In this review, we update the present knowledge on dopamine and dopamine receptors and their potential roles in nausea and vomiting. The pre- and clinical evidence provided in this review supports the implication of both dopamine and dopamine receptor agonists in the incidence of emesis. Besides the conventional dopaminergic antiemetic drugs, potential novel antiemetic targeting emetic protein signaling cascades may offer superior selectivity profile and potency.
Topics: Animals; Antiemetics; Dopamine; Dopamine Agonists; Dopamine D2 Receptor Antagonists; Humans; Receptors, Dopamine D2; Receptors, Dopamine D3; Signal Transduction; Vomiting
PubMed: 32814171
DOI: 10.1016/j.phrs.2020.105124 -
Journal of Pharmacological Sciences Feb 2022An aging society leads to an increased number of patients with cognitive and movement disorders, such as Parkinson's disease and dementia with Lewy bodies. α-Synuclein... (Review)
Review
An aging society leads to an increased number of patients with cognitive and movement disorders, such as Parkinson's disease and dementia with Lewy bodies. α-Synuclein accumulation in neuronal cells is a pathological hallmark of α-synucleinopathies. Aberrant soluble oligomeric units of α-synuclein are toxic and disrupt neuronal homeostasis. Fatty acids partially regulate α-synuclein accumulation as well as oligomerization, and fatty acid-binding protein (FABP) associates with the α-synuclein aggregates. Heart-type FABP (hFABP, FABP3) is rich in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D), which is abundant in caveolae. We recently demonstrated that mesencephalic neurons require FABP3 and dopamine D receptors for the caveolae-mediated α-synuclein uptake. Accumulated α-synuclein gets fibrillized and tightly co-localizes with FABP3 and dopamine D receptors, which leads to mitochondrial dysfunction and loss of tyrosine hydroxylase, a rate-limiting enzyme in dopamine production. Furthermore, the inhibition of FABP3 using small-molecule ligands successfully prevents FABP3-induced neurotoxicity. In this review, we focus on the impact of FABP3, dopamine receptors, and other FABP family proteins in the process of α-synuclein propagation and the subsequent aggregate-induced cytotoxicity. We also propose the potential of FABP as a therapeutic target for α-synucleinopathies.
Topics: Dopamine; Fatty Acid Binding Protein 3; Fatty Acid-Binding Proteins; Humans; Mitochondria; Molecular Targeted Therapy; Protein Aggregates; Receptors, Dopamine; Synucleinopathies; alpha-Synuclein
PubMed: 35063140
DOI: 10.1016/j.jphs.2021.12.003 -
European Journal of Pharmacology Aug 2022Dopamine levels in the central nervous system change under pathological conditions such as Parkinson's disease, Huntington's disease, and addiction. Under those...
Dopamine levels in the central nervous system change under pathological conditions such as Parkinson's disease, Huntington's disease, and addiction. Under those pathological conditions, astrocytes become reactive astrocytes characterized by morphological changes and the release of inflammatory cytokines involved in pathogenesis. However, it remains unclear whether dopamine regulates astrocytic morphology and functions. Elucidating these issues will help us to understand the pathogenesis of neurodegenerative diseases caused by abnormal dopamine signaling. In this study, we investigated the effects of dopamine on IL-6 expression and process formation in rat primary cultured astrocytes and acute hippocampal slices. Dopamine increased IL-6 expression in a concentration-dependent manner, and this was accompanied by CREB phosphorylation. The effects of a low dopamine concentration (1 μM) were inhibited by a D1-like receptor antagonist, whereas the effects of a high dopamine concentration (100 μM) were inhibited by a β-antagonist and enhanced by a D2-like receptor antagonist. Furthermore, dopamine (100 μM) promoted process formation, which was inhibited by a β-antagonist and enhanced by both an α-antagonist and a D2-like receptor antagonist. In acute hippocampal slices, both a D1-like receptor agonist and β-agonist changed astrocytic morphology. Together, these results indicate that dopamine promotes IL-6 expression and process formation via D1-like receptors and β-adrenoceptors. Furthermore, bidirectional regulation exists; namely, the effects of D1-like receptors and β-adrenoceptors were negatively regulated by D2-like receptors and α-adrenoceptors.
Topics: Animals; Astrocytes; Dopamine; Dopamine Agonists; Interleukin-6; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha-2; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35738452
DOI: 10.1016/j.ejphar.2022.175110 -
Neurobiology of Disease Oct 2023L-DOPA-induced dyskinesia (LID) remains a major complication of Parkinson's disease management for which better therapies are necessary. The contribution of the...
L-DOPA-induced dyskinesia (LID) remains a major complication of Parkinson's disease management for which better therapies are necessary. The contribution of the striatonigral direct pathway to LID is widely acknowledged but whether the striatopallidal pathway is involved remains debated. Selective optogenetic stimulation of striatonigral axon terminals induces dyskinesia in mice rendered hemiparkinsonian with the toxin 6-hydroxydopamine (6-OHDA). Here we show that optogenetically-induced dyskinesia is increased by the D2-type dopamine receptor agonist quinpirole. Although the quinpirole effect may be mediated by D2 receptor stimulation in striatopallidal neurons, alternative mechanisms may be responsible as well. To selectively modulate the striatopallidal pathway, we selectively expressed channelrhodopsin-2 (ChR2) in D2 receptor expressing neurons by crossing D2-Cre and ChR2-flox mice. The animals were rendered hemiparkinsonian and implanted with an optic fiber at the ipsilateral external globus pallidus (GPe). Stimulation of ChR2 at striatopallidal axon terminals reduced LID and also general motility during the off L-DOPA state, without modifying the pro-motor effect of low doses of L-DOPA producing mild or no dyskinesia. Overall, the present study shows that D2-type dopamine receptors and the striatopallidal pathway modulate dyskinesia and suggest that targeting striatopallidal axon terminals at the GPe may have therapeutic potential in the management of LID.
Topics: Animals; Mice; Levodopa; Quinpirole; Dopamine Agonists; Dyskinesias; Oxidopamine; Receptors, Dopamine D2
PubMed: 37683958
DOI: 10.1016/j.nbd.2023.106278 -
Anti-cancer Agents in Medicinal... 2021Dopamine Receptor (DR) gene family play an essential role in the regulation of Interleukin- 6 (IL-6) production. Our prior analysis of human prostate biopsy samples...
BACKGROUND
Dopamine Receptor (DR) gene family play an essential role in the regulation of Interleukin- 6 (IL-6) production. Our prior analysis of human prostate biopsy samples demonstrated the increased expression of IL-6 and a downregulating trend for dopamine receptor gene family.
OBJECTIVE
The objective was to investigate the expression of dopamine receptors, their catabolizing enzyme and IL-6 in prostate cancer cell lines and assess pharmacological effect of dopamine receptor modulators as a novel class of drugs repurposed for the treatment of prostate cancer.
METHODS
The therapeutic effect of dopamine, DR agonists, and DR antagonist were examined using LNCaP and PC3 cell lines. Cell viability and proliferation were assessed by MTT assay and proliferating cell nuclear antigen expression analysis, respectively. Furthermore, bax/bcl2 ratio, immunofluorescence assay and flow cytometric assay were performed for apoptosis analysis. RT- qPCR analysis was used to characterize the relative expression of dopamine-related genes, catabolic enzyme Catechol-o-Methyl-Transferase (COMT) and IL-6 before and after treatment to assess the therapeutic effects of drugs.
RESULTS
LNCaP cells express DRD1, DRD2, DRD5 and COMT genes and PC3 cells only express IL-6 gene. In-vitro, dopamine receptor agonists reduced cell viability of LNCaP and PC3 cells. In contrast, dopamine and dopamine receptor antagonist significantly increased tumor growth in PC3 cells.
CONCLUSION
Our results offer novel suggestion for a pathogenic role of dopamine receptor signaling in prostate cancer adenocarcinoma and indicates that modulators of DR- IL-6 pathway, including FDA-approved drug bromocriptine, might be utilized as novel drug repurposing strategy.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Molecular Structure; Prostatic Neoplasms; Receptors, Dopamine; Structure-Activity Relationship
PubMed: 32867661
DOI: 10.2174/1871520620999200831110243 -
Molecular Biology Reports Dec 2020Orexins-A (OrxA) and -B (OrxB) neuropeptides are synthesized by a group of neurons located in the lateral hypothalamus and adjacent perifornical area, which send their...
Orexins-A (OrxA) and -B (OrxB) neuropeptides are synthesized by a group of neurons located in the lateral hypothalamus and adjacent perifornical area, which send their projections to the mesolimbic dopaminergic (DAergic) system including ventral tegmental area and nucleus accumbens (NAc), where orexin receptors are expressed. NAc plays a central role in reward-seeking behavior and drug abuse. NAc-neurons express dopamine-1 (D1R) and dopamine-2 (D2R) receptors. Orexins bind to their two cognate G-protein-coupled receptors, orexin-receptor type-1 (OrxR) and type-2 (OrxR). Orexin receptor signaling is involved in behaviors such as motivation and addiction. Orexin-containing neurons modulate DAergic activity that is key in synaptic plasticity induced by addictive drugs. However, the effect of OrxA on expression and content of DAergic receptors in NAc is unknown. The purpose of this study was to investigate whether OrxA can alter gene expression and protein levels of D1R/D2R in NAc. Gene expression was evaluated by real-time PCR analysis and protein levels by western blot in rats. The results show that intracerebroventricular (i.c.v.) injection of OrxA increases both gene transcription and protein content of D2R but fails to modify D1R. This effect was also confirmed with OrxA infusion in NAc/Shell. Our results demonstrate for the first time that OrxA induces up-regulation of gene and protein of D2R in NAc. These findings support the hypothesis that OrxA modulates the DAergic transmission and this may serve to understand how orexin signaling enhances DA responses at baseline conditions and in response to psychostimulants.
Topics: Animals; Dopaminergic Neurons; Gene Expression Regulation; Injections, Intraventricular; Male; Nucleus Accumbens; Orexins; Protein Binding; RNA, Messenger; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Signal Transduction; Stereotaxic Techniques
PubMed: 33170427
DOI: 10.1007/s11033-020-05979-2 -
Pharmacology & Therapeutics May 2023With L-DOPA, dopamine agonists such as pramipexole, ropinirole and rotigotine constitute key therapeutic options for the management of motor symptoms of Parkinson's... (Review)
Review
With L-DOPA, dopamine agonists such as pramipexole, ropinirole and rotigotine constitute key therapeutic options for the management of motor symptoms of Parkinson's disease. These compounds exert their beneficial effect on motor behaviours by activating dopamine D-class receptors and thereby compensating for the declining dopaminergic transmission in the dorsal striatum. Despite a strong similarity in their mechanism of action, these three dopamine agonists present distinct clinical profiles, putatively underpinned by differences in their pharmacological properties. In this context, this review aims at contributing to close the gap between clinical observations and data from molecular neuropharmacology by exploring the properties of pramipexole, ropinirole and rotigotine from both the clinical and molecular perspectives. Indeed, this review first summarizes and compares the clinical features of these three dopamine agonists, and then explores their binding profiles at the different dopamine receptor subtypes. Moreover, the signalling profiles of pramipexole, ropinirole and rotigotine at the D receptor are recapitulated, with a focus on biased signalling and the potential therapeutic implications. Overall, this review aims at providing a unifying framework of interpretation for both clinicians and fundamental pharmacologists interested in a deep understanding of the pharmacological properties of pramipexole, ropinirole and rotigotine.
Topics: Humans; Pramipexole; Dopamine Agonists; Dopamine; Receptors, Dopamine; Antiparkinson Agents
PubMed: 36958527
DOI: 10.1016/j.pharmthera.2023.108392 -
American Journal of Physiology. Cell... Jul 2022Retinal pigmented epithelial (RPE) cells play an important role in retinal fibrotic diseases such as proliferative vitreoretinopathy (PVR). The purpose of this study was...
Retinal pigmented epithelial (RPE) cells play an important role in retinal fibrotic diseases such as proliferative vitreoretinopathy (PVR). The purpose of this study was to elucidate the involvement of dopamine receptor signaling in regulating the fibrotic activation of RPE cells. Dopamine receptor expression, the effect of dopamine on fibrotic activity, and dopamine production were measured in the human RPE cell line ARPE-19. The fibrotic activation of RPE cells was evaluated in response to treatments with selective dopamine receptor agonists and antagonists by measuring gene expression, migration, proliferation, and fibronectin deposition. and are the dominant dopaminergic receptors expressed in ARPE-19 cells and TGF-β stimulation enhances the autocrine release of dopamine, which we show further exasperates fibrotic activation. Finally, treatment with D2 dopamine receptor antagonists or D5 dopamine receptor agonists inhibits profibrotic gene expression, migration, proliferation, and fibronectin deposition and thus may serve as effective mechanisms for treating retinal fibrosis including PVR.
Topics: Cell Movement; Dopamine; Dopamine Agonists; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibronectins; Fibrosis; Humans; Receptors, Dopamine; Retinal Pigment Epithelium; Vitreoretinopathy, Proliferative
PubMed: 35544697
DOI: 10.1152/ajpcell.00468.2021