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Antioxidants & Redox Signaling Mar 2021The kidney plays an important role in the long-term control of blood pressure. Oxidative stress is one of the fundamental mechanisms responsible for the development of... (Review)
Review
The kidney plays an important role in the long-term control of blood pressure. Oxidative stress is one of the fundamental mechanisms responsible for the development of hypertension. Dopamine, five subtypes of receptors, plays an important role in the control of blood pressure by various mechanisms, including the inhibition of oxidative stress. Dopamine receptors exert their regulatory function to decrease the oxidative stress in the kidney and ultimately maintain normal sodium balance and blood pressure homeostasis. An aberration of this regulation may be involved in the pathogenesis of hypertension. Our present article reviews the important role of oxidative stress and intrarenal dopaminergic system in the regulation of blood pressure, summarizes the current knowledge on renal dopamine receptor-mediated antioxidation, including decreasing reactive oxygen species production, inhibiting pro-oxidant enzyme nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and stimulating antioxidative enzymes, and also discusses its underlying mechanisms, including the increased activity of G protein-coupled receptor kinase 4 (GRK4) and abnormal trafficking of renal dopamine receptors in hypertensive status. Identifying the mechanisms of renal dopamine receptors in the regulation of oxidative stress and their contribution to the pathogenesis of hypertension remains an important research focus. Increased understanding of the role of reciprocal regulation between renal dopamine receptors and oxidative stress in the regulation of blood pressure may give us novel insights into the pathogenesis of hypertension and provide a new treatment strategy for hypertension.
Topics: Antioxidants; Blood Pressure; Dopamine; G-Protein-Coupled Receptor Kinase 4; Hypertension; Kidney; NADPH Oxidases; Oxidative Stress; Phosphorylation; Reactive Oxygen Species; Receptors, Dopamine
PubMed: 32349533
DOI: 10.1089/ars.2020.8106 -
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 -
Neuroscience Letters Jan 2019The dopamine (DA) system is considered to be centrally involved in the pathophysiology of several major psychiatric disorders. Using positron emission tomography (PET),... (Review)
Review
The dopamine (DA) system is considered to be centrally involved in the pathophysiology of several major psychiatric disorders. Using positron emission tomography (PET), aberrations in dopamine D2/D3-receptors (D2-R) levels and uptake of the DA precursor FDOPA have been shown for schizophrenia, substance abuse and depression. Radioligands for the dopamine D1-receptor (D1-R) have been available for more than three decades, however this receptor subtype has received much less attention in psychiatry research. Here, studies investigating D1-R in psychiatric patients in comparison to healthy control subjects are summarized. Although small sample sizes, medication effects and heterogeneous methods of quantification limit the conclusions that can be drawn, the data is suggestive of higher levels of cortical D1-R in drug naïve patients with psychosis, and lower D1-R in patients with affective disorders. Data sharing and reanalysis using harmonized methodology are important next steps towards clarifying the role of D1-R in these disorders.
Topics: Brain; Case-Control Studies; Humans; Mental Disorders; Positron-Emission Tomography; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 29518542
DOI: 10.1016/j.neulet.2018.03.007 -
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 -
The Journal of Biological Chemistry Apr 2023The histamine H3 receptor (H3R) is highly enriched in the spiny projection neurons (SPNs) of the striatum, in both the D1 receptor (D1R)-expressing and D2 receptor...
The histamine H3 receptor (H3R) is highly enriched in the spiny projection neurons (SPNs) of the striatum, in both the D1 receptor (D1R)-expressing and D2 receptor (D2R)-expressing populations. A crossantagonistic interaction between H3R and D1R has been demonstrated in mice, both at the behavioral level and at the biochemical level. Although interactive behavioral effects have been described upon coactivation of H3R and D2R, the molecular mechanisms underlying this interaction are poorly understood. Here, we show that activation of H3R with the selective agonist R-(-)-α-methylhistamine dihydrobromide mitigates D2R agonist-induced locomotor activity and stereotypic behavior. Using biochemical approaches and the proximity ligation assay, we demonstrated the existence of an H3R-D2R complex in the mouse striatum. In addition, we examined consequences of simultaneous H3R-D2R agonism on the phosphorylation levels of several signaling molecules using immunohistochemistry. H3R agonist treatment modulated Akt (serine/threonine PKB)-glycogen synthase kinase 3 beta signaling in response to D2R activation via a β-arrestin 2-dependent mechanism in D2R-SPNs but not in D1R-SPNs. Phosphorylation of mitogen- and stress-activated protein kinase 1 and rpS6 (ribosomal protein S6) was largely unchanged under these conditions. As Akt-glycogen synthase kinase 3 beta signaling has been implicated in several neuropsychiatric disorders, this work may help clarify the role of H3R in modulating D2R function, leading to a better understanding of pathophysiology involving the interaction between histamine and dopamine systems.
Topics: Animals; Mice; Corpus Striatum; Glycogen Synthase Kinase 3 beta; Proto-Oncogene Proteins c-akt; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Histamine H3; Signal Transduction
PubMed: 36871761
DOI: 10.1016/j.jbc.2023.104583 -
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 -
International Journal of Molecular... May 2018Some dopamine receptor subtypes were reported to participate in autophagy regulation, but their exact functions and mechanisms are still unclear. Here we found that...
Some dopamine receptor subtypes were reported to participate in autophagy regulation, but their exact functions and mechanisms are still unclear. Here we found that dopamine receptors D2 and D3 (D2-like family) are positive regulators of autophagy, while dopamine receptors D1 and D5 (D1-like family) are negative regulators. Furthermore, dopamine and ammonia, the two reported endogenous ligands of dopamine receptors, both can induce dopamine receptor internalization and degradation. In addition, we found that AKT (protein kinase B)-mTOR (mechanistic target of rapamycin) and AMPK (AMP-activated protein kinase) pathways are involved in DRD3 (dopamine receptor D3) regulated autophagy. Moreover, autophagy machinery perturbation inhibited DRD3 degradation and increased DRD3 oligomer. Therefore, our study investigated the functions and mechanisms of dopamine receptors in autophagy regulation, which not only provides insights into better understanding of some dopamine receptor-related neurodegeneration diseases, but also sheds light on their potential treatment in combination with autophagy or mTOR pathway modulations.
Topics: AMP-Activated Protein Kinase Kinases; Ammonia; Autophagy; Dopamine Agents; HEK293 Cells; HeLa Cells; Humans; Protein Kinases; Proto-Oncogene Proteins c-akt; Receptors, Dopamine; TOR Serine-Threonine Kinases
PubMed: 29786666
DOI: 10.3390/ijms19051540 -
International Journal of Molecular... Apr 2021Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present differences in both clinical progression and response to drug therapy that are partly affected by genetic factors. Despite extensive knowledge on genetic variability of dopaminergic receptors (DR), few studies have addressed their relevance as possible influencers of clinical heterogeneity in PD patients. In this review, we summarized available evidence regarding the role of genetic polymorphisms in DR as possible determinants of PD development, progression and treatment response. Moreover, we examined the role of DR in the modulation of peripheral immunity, in light of the emerging role of the peripheral immune system in PD pathophysiology. A better understanding of all these aspects represents an important step towards the development of precise and personalized disease-modifying therapies for PD.
Topics: Humans; Parkinson Disease; Polymorphism, Genetic; Receptors, Dopamine
PubMed: 33917417
DOI: 10.3390/ijms22073781 -
Current Neuropharmacology Jan 2018Dopamine D2 and D3 receptors can form homo- and heterodimers and are important targets in Schizophrenia and Parkinson's. Recently, many efforts have been made to... (Review)
Review
BACKGROUND
Dopamine D2 and D3 receptors can form homo- and heterodimers and are important targets in Schizophrenia and Parkinson's. Recently, many efforts have been made to pharmacologically target these receptor complexes. This review focuses on various strategies to act specifically on dopamine receptor dimers, that are transiently formed.
METHODS
Various binding and functional assays were reviewed to study the properties of bivalent ligands, particularly for the dualsteric compound SB269,652. The dimerization of D2 and D3 receptors were analyzed by using single particle tracking microscopy.
RESULTS
The specific targeting of dopamine D2 and D3 dimers can be achieved with bifunctional ligands, composed of two pharmacophores binding the two orthosteric sites of the dimeric complex. If the target is a homodimer, then the ligand is homobivalent. Instead, if the target is a heterodimer, then the ligand is heterobivalent. However, there is some concern regarding pharmacokinetics and binding properties of such drugs. Recently, a new generation of bitopic compounds with dualsteric properties have been discovered that bind to the orthosteric and the allosteric sites in one monomeric receptor. Regarding dopamine D2 and D3 receptors, a new dualsteric molecule SB269,652 was shown to have selective negative allosteric properties across D2 and D3 homodimers, but it behaves as an orthosteric antagonist on receptor monomer. Targeting dimers is also complicated as they are transiently formed with varying monomer/dimer ratio. Furthermore, this ratio can be altered by administering an agonist or a bifunctional antagonist.
CONCLUSION
Last 15 years have witnessed an explosive amount of work aimed at generating bifunctional compounds as a novel strategy to target GPCR homo- and heterodimers, including dopamine receptors. Their clinical use is far from trivial, but, at least, they have been used to validate the existence of receptor dimers in-vitro and in-vivo. The dualsteric compound SB269, 652, with its peculiar pharmacological profile, may offer therapeutic advantages and a better tolerability in comparison with pure antagonists at D2 and D3 receptors and pave the way for a new generation of antipsychotic drugs.
Topics: Allosteric Regulation; Allosteric Site; Animals; Antipsychotic Agents; Dimerization; Dopamine Agents; Humans; Ligands; Mental Disorders; Protein Binding; Receptors, Dopamine D2
PubMed: 28521704
DOI: 10.2174/1570159X15666170518151127 -
Tijdschrift Voor Psychiatrie 2021Current antipsychotic treatment is suboptimal. There is an urgent need for new antipsychotics with new mechanisms of action. SEP-363856 is a trace amine-associated... (Review)
Review
BACKGROUND
Current antipsychotic treatment is suboptimal. There is an urgent need for new antipsychotics with new mechanisms of action. SEP-363856 is a trace amine-associated receptor 1 (TAAR1) agonist and a serotonin 5-HT1a agonist with potential antipsychotic properties.
AIM
To describe the rationale for the development of SEP-363856, the pharmacology of TAAR1/5-HT1a agonists, and the clinical efficacy of SEP-363856.
METHOD
A narrative review of the literature using PubMed, Embase and PsychINFO.
RESULTS
Six publications were identified, one of which was a phase 2 clinical trial with SEP-363856. This phase 2 study shows that SEP-363856 is an effective and well-tolerated antipsychotic; positive, but also negative symptoms decreased; motor side effects (akathisia) and prolactin increase did not occur, while metabolic side effects hardly occurred. Reported side-effects were somnolence and nausea. The antipsychotic activity of SEP-363856 appears to be (pre)clinical not based on D2 antagonism, but on TAAR1 and 5-HT1a agonism.
CONCLUSION
TAAR1 and 5-HT1a agonists such as SEP-363856 may be a treatment option for psychosis. Hopefully they can be further developed into an antipsychotic with a favorable effectiveness and tolerability profile.
Topics: Antipsychotic Agents; Humans; Psychotic Disorders; Receptors, Dopamine; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome
PubMed: 34851520
DOI: No ID Found