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Pathology Oncology Research : POR Jul 2020In preclinical studies serotonin stimulates and dopamine inhibits tumour growth and angiogenesis. Information regarding serotonin and dopamine receptor (5-HTR and DRD)...
In preclinical studies serotonin stimulates and dopamine inhibits tumour growth and angiogenesis. Information regarding serotonin and dopamine receptor (5-HTR and DRD) expression in human cancers is limited. Therefore, we screened a large tumour set for receptor mRNA overexpression using functional genomic mRNA (FGmRNA) profiling, and we analysed protein expression and location of 5-HTR1B, 5-HTR2B, DRD1, and DRD2 with immunohistochemistry in different tumour types. With FGmRNA profiling 11,756 samples representing 43 tumour types were compared to 3,520 normal tissue samples to analyse receptor overexpression. 5-HTR2B overexpression was present in many tumour types, most frequently in uveal melanomas (56%). Receptor overexpression in rare cancers included 5-HTR1B in nasopharyngeal carcinoma (17%), DRD1 in ependymoma (30%) and synovial sarcoma (21%), and DRD2 in astrocytoma (13%). Immunohistochemistry demonstrated high 5-HTR2B protein expression on melanoma and gastro-intestinal stromal tumour cells and endothelial cells of colon, ovarian, breast, renal and pancreatic tumours. 5-HTR1B expression was predominantly low. High DRD2 protein expression on tumour cells was observed in 48% of pheochromocytomas, and DRD1 expression ranged from 14% in melanoma to 57% in renal cell carcinoma. In conclusion, 5-HTR1B, 5-HTR2B, DRD1, and DRD2 show mRNA overexpression in a broad spectrum of common and rare cancers. 5-HTR2B protein is frequently highly expressed in human cancers, especially on endothelial cells. These findings support further investigation of especially 5HTR2B as a potential treatment target.
Topics: Biomarkers, Tumor; Humans; Neoplasms; Receptors, Dopamine; Receptors, Serotonin
PubMed: 31478179
DOI: 10.1007/s12253-019-00734-w -
Bioorganic & Medicinal Chemistry Letters Apr 2022The dopamine receptor 4 (DR) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the...
The dopamine receptor 4 (DR) is highly expressed in both motor, associative and limbic subdivisions of the cortico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the DR in the modulation of this network and its subsequent involvement in l-DOPA induced dyskinesias in Parkinson's disease. As part of our continued effort in the discovery of novel DR antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as DR antagonists. We report several DR selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported DR antagonists.
Topics: Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Piperidines; Receptors, Dopamine D4; Structure-Activity Relationship
PubMed: 35151866
DOI: 10.1016/j.bmcl.2022.128615 -
Molecular Cell Mar 2021The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors...
The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders. Here, we report two cryo-EM structures of human D3R in complex with an inhibitory G protein and bound to the D3R-selective agonists PD128907 and pramipexole, the latter of which is used to treat patients with Parkinson's disease. The structures reveal agonist binding modes distinct from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling illuminate determinants of ligand specificity across dopamine receptors and the mechanisms for G protein coupling. Collectively our work reveals the basis of agonist binding and ligand-induced receptor activation and provides structural templates for designing specific ligands to treat CNS diseases targeting the dopaminergic system.
Topics: Benzopyrans; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gi-Go; HEK293 Cells; Humans; Models, Molecular; Multiprotein Complexes; Oxazines; Pramipexole; Protein Domains; Receptors, Dopamine D3; Structure-Activity Relationship
PubMed: 33548201
DOI: 10.1016/j.molcel.2021.01.003 -
Biomolecules Mar 2021Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not...
Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not discriminate among different DR subtypes and may even stimulate alpha1 and beta-adrenoceptors. Here, we tested the hypothesis that D2R and/or D3R may specifically induce vasoconstriction in isolated mouse aorta. Aorta, isolated from wild-type (WT) and D3R/ mice, was mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE), acetylcholine (ACh), and the D3R agonist 7-hydrxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT), with or without the D2R antagonist L741,626 and the D3R antagonist SB-277011-A. The vasoconstriction to PE and the vasodilatation to ACh were not different in WT and D3R/; in contrast, the contractile responses to 7-OH-DPAT were significantly weaker in D3R/, though not abolished. L741,626 did not change the contractile response induced by 7-OH-DPAT in WT or in D3R/, whereas SB-277011-A significantly reduced it in WT but did not in D3R/. D3R mRNA (assessed by qPCR) was about 5-fold more abundant than D2R mRNA in aorta from WT and undetectable in aorta from D3R/. Following transduction with lentivirus (72-h incubation) delivering synthetic microRNAs to specifically inactivate D2R (LV-miR-D2) or D3R (LV-miR-D3), the contractile response to 7-OH-DPAT was unaffected by LV-miR-D2, while it was significantly reduced by LV-miR-D3. These data indicate that, at least in mouse aorta, D3R stimulation induces vasoconstriction, while D2R stimulation does not. This is consistent with the higher expression level of D3R. The residual vasoconstriction elicited by high concentration D3R agonist in D3R/ and/or in the presence of D3R antagonist is likely to be unrelated to DRs.
Topics: Animals; Aorta; Indoles; Male; Mice, Inbred C57BL; Mice, Knockout; Nitriles; Piperidines; RNA, Messenger; Receptors, Dopamine D2; Receptors, Dopamine D3; Tetrahydroisoquinolines; Tetrahydronaphthalenes; Vasoconstriction; Mice
PubMed: 33799860
DOI: 10.3390/biom11030418 -
Brain, Behavior and Evolution 2015Dopamine neurotransmission regulates various brain functions, and its regulatory roles are mediated by two families of G protein-coupled receptors: the D1 and D2... (Review)
Review
Dopamine neurotransmission regulates various brain functions, and its regulatory roles are mediated by two families of G protein-coupled receptors: the D1 and D2 receptor families. In mammals, the D1 family comprises two receptor subtypes (D1 and D5), while the D2 family comprises three receptor subtypes (D2, D3 and D4). Phylogenetic analyses of dopamine receptor genes strongly suggest that the common ancestor of Osteichthyes (bony jawed vertebrates) possessed four subtypes in the D1 family and five subtypes in the D2 family. Mammals have secondarily lost almost half of the ancestral dopamine receptor genes, whereas nonmammalian species kept many of them. Although the mammalian situation is an exception among Osteichthyes, the current classification and characterization of dopamine receptors are based on mammalian features, which have led to confusion in the identification of dopamine receptor subtypes in nonmammalian species. Here we begin by reviewing the history of the discovery of dopamine receptors in vertebrates. The recent genome sequencing of coelacanth, gar and elephant shark led to the proposal of a refined scenario of evolution of dopamine receptor genes. We also discuss a current problem of nomenclature of dopamine receptors. Following the official nomenclature of mammalian dopamine receptors from D1 to D5, we propose to name newly identified receptor subtypes from D6 to D9 in order to facilitate the use of an identical name for orthologous genes among different species. To promote a nomenclature change which allows distinguishing the two dopamine receptor families, a nomenclature consortium is needed. This comparative perspective is crucial to correctly interpret data obtained in animal studies on dopamine-related brain disorders, and more fundamentally, to understand the characteristics of dopamine neurotransmission in vertebrates.
Topics: Animals; Biological Evolution; Fish Proteins; Fishes; Receptors, Dopamine; Terminology as Topic
PubMed: 26613258
DOI: 10.1159/000441550 -
Current Topics in Behavioral... 2023Parkinson disease (PD) dementia, pathologically featured as nigrostriatal dopamine (DA) neuronal loss with motor and non-motor manifestations, leads to substantial...
Parkinson disease (PD) dementia, pathologically featured as nigrostriatal dopamine (DA) neuronal loss with motor and non-motor manifestations, leads to substantial disability and economic burden. DA therapy targets the DA D3 receptor (D3R) with high affinity and selectivity. The pathological involvement of D3R is evidenced as an effective biomarker for disease progression and DA agnostic interventions, with compensations of increased DA, decreased aggregates of α-synuclein (α-Syn), enhanced secretion of brain-derived neurotrophic factors (BDNF), attenuation of neuroinflammation and oxidative damage, and promoting neurogenesis in the brain. D3R also interacts with D1R to reduce PD-associated motor symptoms and alleviate the side effects of levodopa (L-DOPA) treatment. We recently found that DA D2 receptor (D2R) density decreases in the late-stage PDs, while high D3R or DA D1 receptor (D1R) + D3R densities in the postmortem PD brains correlate with survival advantages. These new essential findings warrant renewed investigations into the understanding of D3R neuron populations and their cross-sectional and longitudinal regulations in PD progression.
Topics: Humans; Parkinson Disease; Receptors, Dopamine D3; Cross-Sectional Studies; Dopamine; Receptors, Dopamine D1; Prognosis
PubMed: 35711029
DOI: 10.1007/7854_2022_373 -
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 -
Cellular Signalling Jan 2018Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists)... (Review)
Review
Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists) and Parkinson's disease (agonists). However, as the DR and DR subtypes are highly homologous, creating compounds with sufficient subtype-selectivity as well as drug-like properties for therapeutic use has proved challenging. This review summarizes the progress that has been made in developing DR- or DR-selective antagonists and agonists, and also describes the experimental conditions that need to be considered when determining the selectivity of a given compound, as apparent selectivity can vary widely depending on assay conditions. Future advances in this field may take advantage of currently available structural data to target alternative secondary binding sites through creating bivalent or bitopic chemical structures. Alternatively, the use of high-throughput screening techniques to identify novel scaffolds that might bind to the DR or DR in areas other than the highly conserved orthosteric site, such as allosteric sites, followed by iterative medicinal chemistry will likely lead to exceptionally selective compounds in the future. More selective compounds will provide a better understanding of the normal and pathological functioning of each receptor subtype, as well as offer the potential for improved therapeutics.
Topics: Allosteric Site; Animals; Antiparkinson Agents; Binding Sites; Dopamine Agonists; Drug Design; Humans; Molecular Structure; Parkinson Disease; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Structure-Activity Relationship
PubMed: 28716664
DOI: 10.1016/j.cellsig.2017.07.003 -
Biomolecules Jan 2021Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong... (Review)
Review
Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson's disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.
Topics: Animals; Biomedical Research; Brain; Central Nervous System Diseases; Humans; Neurons; Receptors, Dopamine D3; Translational Research, Biomedical
PubMed: 33466844
DOI: 10.3390/biom11010104 -
Translational Psychiatry Mar 2016The D2 dopamine receptor mediates neuropsychiatric symptoms and is a target of pharmacotherapy. Inter-individual variation of D2 receptor density is thought to influence... (Meta-Analysis)
Meta-Analysis Review
The D2 dopamine receptor mediates neuropsychiatric symptoms and is a target of pharmacotherapy. Inter-individual variation of D2 receptor density is thought to influence disease risk and pharmacological response. Numerous molecular imaging studies have tested whether common genetic variants influence D2 receptor binding potential (BP) in humans, but demonstration of robust effects has been limited by small sample sizes. We performed a systematic search of published human in vivo molecular imaging studies to estimate effect sizes of common genetic variants on striatal D2 receptor BP. We identified 21 studies examining 19 variants in 11 genes. The most commonly studied variant was a single-nucleotide polymorphism in ANKK1 (rs1800497, Glu713Lys, also called 'Taq1A'). Fixed- and random-effects meta-analyses of this variant (5 studies, 194 subjects total) revealed that striatal BP was significantly and robustly lower among carriers of the minor allele (Lys713) relative to major allele homozygotes. The weighted standardized mean difference was -0.57 under the fixed-effect model (95% confidence interval=(-0.87, -0.27), P=0.0002). The normal relationship between rs1800497 and BP was not apparent among subjects with neuropsychiatric diseases. Significant associations with baseline striatal D2 receptor BP have been reported for four DRD2 variants (rs1079597, rs1076560, rs6277 and rs1799732) and a PER2 repeat polymorphism, but none have yet been tested in more than two independent samples. Our findings resolve apparent discrepancies in the literature and establish that rs1800497 robustly influences striatal D2 receptor availability. This genetic variant is likely to contribute to important individual differences in human striatal function, neuropsychiatric disease risk and pharmacological response.
Topics: Brain; Genetic Variation; Humans; Molecular Imaging; Positron-Emission Tomography; Receptors, Dopamine D2; Tomography, Emission-Computed, Single-Photon
PubMed: 26926883
DOI: 10.1038/tp.2016.22