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BMC Cancer Dec 2022Dopamine receptors have been reported to play important roles in cancer progression. However, the role of dopamine receptor D3 (DRD3) in hepatocellular carcinoma (HCC)...
BACKGROUND
Dopamine receptors have been reported to play important roles in cancer progression. However, the role of dopamine receptor D3 (DRD3) in hepatocellular carcinoma (HCC) remains unclear.
METHODS
The expression of DRD3 was detected by immunohistochemistry and real-time qPCR. The prognostic value of DRD3 in patients was investigated by analyzing selected databases, including cBioPortal and Kaplan-Meier plotter. Cell growth was tested by CCK8 assay, and Transwell assays were performed to assess cancer cell migration and invasion. The cAMP/ERK/CREB signaling pathway was evaluated by Western blot analysis and ELISA. An HCC xenograft model was established for in vivo experiments.
RESULTS
DRD3 mRNA expression was significantly higher in nontumor tissues than in tumor tissues. Lower protein expression of DRD3 was related to poor recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier plotter analysis showed that higher expression of DRD3 mRNA was associated with better OS, RFS, disease-specific survival (DSS), and progression-free survival (PFS). cBioPortal analysis revealed that the alteration group, which harbored genetic mutations in DRD3, exhibited poor OS, RFS, DSS and PFS. According to CCK8 and Transwell assays, stable DRD3 overexpression cell line (ex-DRD3-SK-HEP-1) showed weaker proliferation, migration and invasion behaviors. PD128907, a DRD3 agonist, suppressed proliferation, migration and invasion in HCC cell lines, while U99194, a DRD3 antagonist, enhanced proliferation, migration and invasion in HCC cell lines. Western blot analysis and ELISA revealed that stable DRD3 knock-down cell line (sh-DRD3-PLC/PRF/5) and U99194 both increased the protein levels of cAMP, p-ERK and p-CREB; on the other hand, ex-DRD3-SK-HEP-1 and PD128907 decreased the protein levels of cAMP, p-ERK and p-CREB. SCH772984, an ERK antagonist, abolished the effect of U99194 on the malignant biological behaviors of HCC cells. In vivo, PD128907 suppressed tumor growth, and U99194 enhanced tumor growth.
CONCLUSION
Our results suggest that down-regulation of DRD3 is strongly involved in the progression of HCC, and DRD3 might be consider as an independent prognostic factor for HCC. Furthermore, DRD3 agonists may be a promising strategy for HCC therapy.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Receptors, Dopamine D3; RNA, Messenger
PubMed: 36456906
DOI: 10.1186/s12885-022-10368-y -
Technology in Cancer Research &... 2021The dopamine receptors (DRs) family includes 5 members with differences in signal transduction and ligand affinity. Abnormal DRs expression has been correlated multiple... (Review)
Review
The dopamine receptors (DRs) family includes 5 members with differences in signal transduction and ligand affinity. Abnormal DRs expression has been correlated multiple tumors with their clinical outcome. Thus, it has been proposed that DRs-targeting drugs-developed for other diseases as schizophrenia or Parkinson's disease-could be helpful in managing neoplastic diseases. In this review, we discuss the role of DRs and the effects of DRs-targeting in tumor progression and cancer cell biology using multiple high-prevalence neoplasms as examples. The evidence shows that DRs are valid therapeutic targets for certain receptor/disease combinations, but the data are inconclusive or contradictory for others. In either case, further studies are required to define the precise role of DRs in tumor progression and propose better therapeutic strategies for their targeting.
Topics: Animals; Dopamine Agonists; Dopamine Antagonists; Humans; Molecular Targeted Therapy; Neoplasms; Receptors, Dopamine; Signal Transduction
PubMed: 34212819
DOI: 10.1177/15330338211027913 -
ACS Chemical Neuroscience Mar 2020Kinetic analysis of dopamine receptor activation and inactivation and the study of dopamine-dependent signaling requires precise simulation of the presynaptic release of...
Kinetic analysis of dopamine receptor activation and inactivation and the study of dopamine-dependent signaling requires precise simulation of the presynaptic release of the neurotransmitter dopamine and tight temporal control over the release of dopamine receptor antagonists. The 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group was conjugated to dopamine and the dopamine receptor antagonist sulpiride to generate "caged" versions of these neuromodulators (CyHQ--DA and CyHQ-sulpiride, respectively) that could release their payloads with 365 or 405 nm light or through 2-photon excitation (2PE) at 740 nm. These compounds are stable under physiological conditions in the dark, yet photolyze rapidly and cleanly to yield dopamine or sulpiride and the caging remnant CyHQ-OH. CyHQ--DA mediated the light activation of dopamine-1 (D1) receptors on the breast cancer cell line MDA-MB-231 in culture. In mouse brain slice from the substantia nigra pars compacta, localized flash photolysis of CyHQ--DA accurately mimicked the natural presynaptic release of dopamine and activation of dopamine-2 (D2) receptors, causing a robust, concentration-dependent, and repeatable G protein-coupled inwardly rectifying potassium channel-mediated outward current in whole-cell voltage clamp recordings that was amplified by cocaine and blocked by sulpiride. Photolysis of CyHQ-sulpiride rapidly blocked synaptic activity, enabling measurement of the unbinding rates of dopamine and quinpirole, a D2 receptor agonist. These tools will enable more detailed study of dopamine receptors, their interactions with other GPCRs, and the physiology of dopamine signaling in the brain.
Topics: Animals; Dopamine; Dopamine Agonists; Dopaminergic Neurons; Kinetics; Mice; Quinpirole; Receptors, Dopamine D1; Sulpiride
PubMed: 32077679
DOI: 10.1021/acschemneuro.9b00675 -
The FEBS Journal Feb 2017By performing two high-content small molecule screens on dextran sodium sulfate- and trinitrobenzene sulfonic acid-induced zebrafish enterocolitis models of inflammatory...
By performing two high-content small molecule screens on dextran sodium sulfate- and trinitrobenzene sulfonic acid-induced zebrafish enterocolitis models of inflammatory bowel disease, we have identified novel anti-inflammatory drugs from the John Hopkins Clinical Compound Library that suppress neutrophilic inflammation. Live imaging of neutrophil distribution was used to assess the level of acute inflammation and concurrently screen for off-target drug effects. Supporting the validity of our screening strategy, most of the anti-inflammatory drug hits were known antibiotics or anti-inflammatory agents. Novel hits included cholecystokinin (CCK) and dopamine receptor agonists. Using a pharmacological approach, we show that while CCK and dopamine receptor agonists alleviate enterocolitis-associated inflammation, receptor antagonists exacerbate inflammation in zebrafish. This work highlights the utility of small molecule screening in zebrafish enterocolitis models as a tool to identify novel bioactive molecules capable of modulating acute inflammation.
Topics: Animals; Animals, Genetically Modified; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Dextran Sulfate; Disease Models, Animal; Dopamine Agonists; Dysbiosis; Embryo, Nonmammalian; Gene Expression; High-Throughput Screening Assays; Humans; Immunologic Factors; Intestines; Neutrophils; Receptors, Cholecystokinin; Receptors, Dopamine; Small Molecule Libraries; Trinitrobenzenesulfonic Acid; Zebrafish
PubMed: 27885812
DOI: 10.1111/febs.13976 -
Nature Communications Jun 2022An organism's ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity...
An organism's ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction, acts in-part through a cell non-autonomous signaling pathway that is inhibited by the presence of attractive smells. Using an intestinal reporter for a key gene induced by dietary restriction but suppressed by attractive smells, we identify three compounds that block food odor effects in C. elegans, thereby increasing longevity as dietary restriction mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor. We further identify a chemosensory neuron that likely perceives food odor, an enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster. Thus, blocking food odor signaling through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.
Topics: Aging; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Dopamine; Drosophila melanogaster; Longevity; Odorants; Receptors, Dopamine; Serotonin
PubMed: 35672307
DOI: 10.1038/s41467-022-30869-5 -
Clinical Cancer Research : An Official... Apr 2019Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other...
PURPOSE
Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201.
EXPERIMENTAL DESIGN
The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in >1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. IHC staining of DRD2/DRD5 was performed on tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies.
RESULTS
DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from patients with recurrent glioblastoma treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes.
CONCLUSIONS
These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.
Topics: Antineoplastic Agents; Biomarkers; Cell Line, Tumor; Cell Survival; Dopamine D2 Receptor Antagonists; Drug Resistance; Gene Expression; Humans; Imidazoles; Immunohistochemistry; Magnetic Resonance Imaging; Neoplasm Grading; Neoplasm Staging; Neoplasms; Prognosis; Protein Binding; Pyridines; Pyrimidines; Receptors, Dopamine D2; Receptors, Dopamine D5; Signal Transduction
PubMed: 30559168
DOI: 10.1158/1078-0432.CCR-18-2572 -
Movement Disorders : Official Journal... Aug 2021Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine... (Meta-Analysis)
Meta-Analysis Review
Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine receptors emerge as a consequence of the loss of dopamine nerve terminals or dopaminergic pharmacotherapy. We performed a systematic review and meta-analysis of the available PET and single-photon emission computed tomography studies that have investigated dopamine receptors in PD, PSP and MSA. The inclusion criteria were studies including human PET or single-photon emission computed tomography imaging; dopamine receptor tracers (D1-like or D2-like) and idiopathic PD, PSP, or MSA patients compared with healthy controls. The 67 included D2-like studies had 1925 patients. Data were insufficient for an analysis of D1-like studies. PD patients had higher striatal binding early in the disease, but after a disease duration of 4.36 years, PD patients had lower binding values than healthy controls. Striatal D2R binding was highest in unmedicated early PD patients and in the striatum contralateral to the predominant motor symptoms. PSP and MSA-P patients had lower striatal D2R binding than PD patients (14.2% and 21.8%, respectively). There is initial upregulation of striatal D2Rs in PD, which downregulate on average 4 years after motor symptom onset, possibly because of agonist-induced effects. The consistent upregulation of D2Rs in the PD striatum contralateral to the predominant motor symptoms indicates that receptor changes are driven by neurodegeneration and loss of striatal neuropil. Both PSP and MSA patients have clearly lower striatal D2R binding values than PD patients, which offers an opportunity for differential diagnostics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Parkinson Disease; Receptors, Dopamine D2; Tomography, Emission-Computed, Single-Photon
PubMed: 33955044
DOI: 10.1002/mds.28632 -
Scientific Reports Jun 2023The striatum integrates dense neuromodulatory inputs from many brain regions to coordinate complex behaviors. This integration relies on the coordinated responses from...
The striatum integrates dense neuromodulatory inputs from many brain regions to coordinate complex behaviors. This integration relies on the coordinated responses from distinct striatal cell types. While previous studies have characterized the cellular and molecular composition of the striatum using single-cell RNA-sequencing at distinct developmental timepoints, the molecular changes spanning embryonic through postnatal development at the single-cell level have not been examined. Here, we combine published mouse striatal single-cell datasets from both embryonic and postnatal timepoints to analyze the developmental trajectory patterns and transcription factor regulatory networks within striatal cell types. Using this integrated dataset, we found that dopamine receptor-1 expressing spiny projection neurons have an extended period of transcriptional dynamics and greater transcriptional complexity over postnatal development compared to dopamine receptor-2 expressing neurons. Moreover, we found the transcription factor, FOXP1, exerts indirect changes to oligodendrocytes. These data can be accessed and further analyzed through an interactive website ( https://mouse-striatal-dev.cells.ucsc.edu ).
Topics: Animals; Mice; Neurons; Corpus Striatum; Neostriatum; Transcription Factors; Receptors, Dopamine
PubMed: 37270616
DOI: 10.1038/s41598-023-36255-5 -
Bioorganic & Medicinal Chemistry May 2016Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were...
Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n-alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues (10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity. De-rigidification of stepholidine resulted in decreased affinity at all receptors evaluated; thus the tetracyclic THPB framework is advantageous for affinity at dopamine and σ receptors. Docking of the C10 analogues at the D3 receptor, suggest that an ionic interaction between the protonated nitrogen atom and Asp110, a H-bond interaction between the C2 phenol and Ser192, a H-bond interaction between the C10 phenol and Cys181 as well as hydrophobic interactions of the aryl rings to Phe106 and Phe345, are critical for high affinity of the compounds.
Topics: Alkaloids; Berberine; Receptors, Dopamine; Receptors, sigma
PubMed: 27032890
DOI: 10.1016/j.bmc.2016.03.037 -
Biomolecules Oct 2023The D2 dopamine receptor (D2R) signals through both G proteins and β-arrestins to regulate important physiological processes, such as movement, reward circuitry,...
G Protein-Coupled Receptor Kinase 2 Selectively Enhances β-Arrestin Recruitment to the D Dopamine Receptor through Mechanisms That Are Independent of Receptor Phosphorylation.
The D2 dopamine receptor (D2R) signals through both G proteins and β-arrestins to regulate important physiological processes, such as movement, reward circuitry, emotion, and cognition. β-arrestins are believed to interact with G protein-coupled receptors (GPCRs) at the phosphorylated C-terminal tail or intracellular loops. GPCR kinases (GRKs) are the primary drivers of GPCR phosphorylation, and for many receptors, receptor phosphorylation is indispensable for β-arrestin recruitment. However, GRK-mediated receptor phosphorylation is not required for β-arrestin recruitment to the D2R, and the role of GRKs in D2R-β-arrestin interactions remains largely unexplored. In this study, we used GRK knockout cells engineered using CRISPR-Cas9 technology to determine the extent to which β-arrestin recruitment to the D2R is GRK-dependent. Genetic elimination of all GRK expression decreased, but did not eliminate, agonist-stimulated β-arrestin recruitment to the D2R or its subsequent internalization. However, these processes were rescued upon the re-introduction of various GRK isoforms in the cells with GRK2/3 also enhancing dopamine potency. Further, treatment with compound 101, a pharmacological inhibitor of GRK2/3 isoforms, decreased β-arrestin recruitment and receptor internalization, highlighting the importance of this GRK subfamily for D2R-β-arrestin interactions. These results were recapitulated using a phosphorylation-deficient D2R mutant, emphasizing that GRKs can enhance β-arrestin recruitment and activation independently of receptor phosphorylation.
Topics: Arrestins; beta-Arrestins; G-Protein-Coupled Receptor Kinases; Phosphorylation; Protein Isoforms; Receptors, Dopamine; Receptors, G-Protein-Coupled; Humans; HEK293 Cells
PubMed: 37892234
DOI: 10.3390/biom13101552