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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 -
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 -
Expert Opinion on Investigational Drugs 2023Schizophrenia is a severe mental illness comprising positive, negative, and cognitive symptoms. Existing pharmacologic options exert their actions on the dopamine... (Review)
Review
INTRODUCTION
Schizophrenia is a severe mental illness comprising positive, negative, and cognitive symptoms. Existing pharmacologic options exert their actions on the dopamine receptor but are largely ineffective at treating negative and cognitive symptoms. Alternative pharmacologic options that do not act directly on the dopamine receptor are being investigated, including potassium channel modulators. It has been hypothesized that dysfunctional fast-spiking parvalbumin-positive GABA interneurons, regulated by Kv3.1 and Kv3.2 potassium channels, contribute to the symptoms of schizophrenia, making potassium channels an area of clinical interest.
AREAS COVERED
This review will highlight potassium channel modulators for the treatment of schizophrenia, with a focus on AUT00206. Background on Kv3.1 and Kv3.2 potassium channels will be explored. Our search strategy included a literature review utilizing PubMed, Clinicaltrials.gov, and sources available on the manufacturer's website.
EXPERT OPINION
Initial data on potassium channel modulators is promising; however, further study is needed, and existing evidence is limited. Early data suggests that dysfunctional GABA interneurons can be ameliorated through modulators of Kv3.1 and Kv3.2 channels. AUT00206 has been shown to improve dopaminergic dysfunction induced by ketamine and PCP, improve resting gamma power in patients with schizophrenia, impact dopamine synthesis capacity in a subgroup of individuals with schizophrenia, and affect reward anticipation-related neural activation.
Topics: Humans; Potassium Channels; Drugs, Investigational; Schizophrenia; gamma-Aminobutyric Acid; Receptors, Dopamine
PubMed: 37247333
DOI: 10.1080/13543784.2023.2219385 -
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 -
The Journal of Pharmacology and... Sep 2023Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in...
Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in idiopathic pulmonary fibrosis (IPF). This uncontrolled production of ECM is stimulated by mechanosignaling and transforming growth factor beta 1 (TGF-1) signaling that together promote transcriptional programs including Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). G protein-coupled receptors (GPCRs) that couple to G s have emerged as pharmacological targets to inactivate YAP/TAZ signaling and promote lung fibrosis resolution. Previous studies have shown a loss of expression of "antifibrotic GPCRs"-receptors that couple to G s, in IPF patient-derived fibroblasts compared with non-IPF samples. Of the 14 G s GPCRs we found to be expressed in lung fibroblasts, the dopamine receptor D1 () was one of only two not repressed by TGF-1 signaling, with the 2-adrenergic receptor being the most repressed. We compared the potency and efficacy of multiple D1 and 2 receptor agonists +/- TGF-1 treatment in vitro for their ability to elevate cAMP, inhibit nuclear localization of YAP/TAZ, regulate expression of profibrotic and antifibrotic genes, and inhibit cellular proliferation and collagen deposition. Consistently, the activity of 2 receptor agonists was lost, whereas D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-1. These data further support the therapeutic potential of the dopamine receptor D1 and highlight an orchestrated and pervasive loss of antifibrotic GPCRs mediated by TGF-1 signaling. SIGNIFICANCE STATEMENT: Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease with limited therapies. GPCRs have emerged as a primary target for the development of novel antifibrotic drugs; however, a challenge to this approach is the dramatic changes in GPCR expression in response to profibrotic stimuli. Here, we investigate the impact of TGF-1 on the expression of antifibrotic GPCRs and show the D1 dopamine receptor expression is uniquely maintained in response to TGF-1, further implicating it as a compelling target to treat IPF.
Topics: Humans; Fibroblasts; Idiopathic Pulmonary Fibrosis; Lung; Receptors, Dopamine; Receptors, G-Protein-Coupled; Transforming Growth Factor beta; Transforming Growth Factor beta1
PubMed: 37024146
DOI: 10.1124/jpet.122.001442 -
Nature Dec 2021Interactions between the mediodorsal thalamus and the prefrontal cortex are critical for cognition. Studies in humans indicate that these interactions may resolve...
Interactions between the mediodorsal thalamus and the prefrontal cortex are critical for cognition. Studies in humans indicate that these interactions may resolve uncertainty in decision-making, but the precise mechanisms are unknown. Here we identify two distinct mediodorsal projections to the prefrontal cortex that have complementary mechanistic roles in decision-making under uncertainty. Specifically, we found that a dopamine receptor (D2)-expressing projection amplifies prefrontal signals when task inputs are sparse and a kainate receptor (GRIK4) expressing-projection suppresses prefrontal noise when task inputs are dense but conflicting. Collectively, our data suggest that there are distinct brain mechanisms for handling uncertainty due to low signals versus uncertainty due to high noise, and provide a mechanistic entry point for correcting decision-making abnormalities in disorders that have a prominent prefrontal component.
Topics: Animals; Decision Making; Female; Humans; Interneurons; Male; Mediodorsal Thalamic Nucleus; Mice; Neural Pathways; Prefrontal Cortex; Receptors, Dopamine; Receptors, Kainic Acid; Thalamus; Uncertainty
PubMed: 34614503
DOI: 10.1038/s41586-021-04056-3 -
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 -
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 -
International Immunopharmacology Nov 2019Neuroinflammation is a general pathological feature of central nervous system (CNS) diseases, primarily caused by activation of astrocytes and microglia, as well as the... (Review)
Review
Neuroinflammation is a general pathological feature of central nervous system (CNS) diseases, primarily caused by activation of astrocytes and microglia, as well as the infiltration of peripheral immune cells. Inhibition of neuroinflammation is an important strategy in the treatment of brain disorders. Dopamine (DA) receptor, a significant G protein-coupled receptor (GPCR), is classified into two families: D1-like (D1 and D5) and D2-like (D2, D3 and D4) receptor families, according to their downstream signaling pathways. Traditionally, DA receptor forms a wide variety of psychological activities and motor functions, such as voluntary movement, working memory and learning. Recently, the role of DA receptor in neuroinflammation has been investigated widely, mainly focusing on nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, renin-angiotensin system, αB-crystallin, as well as invading peripheral immune cells, including T cells, dendritic cells, macrophages and monocytes. This review briefly outlined the functions and signaling pathways of DA receptor subtypes as well as its role in inflammation-related glial cells, and subsequently summarized the mechanisms of DA receptors affecting neuroinflammation. Meaningfully, this article provided a theoretical basis for drug development targeting DA receptors in inflammation-related brain diseases.
Topics: Animals; Encephalitis; Humans; Neuroglia; Receptors, Dopamine; Signal Transduction
PubMed: 31622861
DOI: 10.1016/j.intimp.2019.105908 -
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