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https://www.readbyqxmd.com/read/28855798/abnormalities-of-dopamine-d3-receptor-signaling-in-the-diseased-brain
#1
REVIEW
G Aleph Prieto
Dopamine D3 receptors (D3R) modulate neuronal activity in several brain regions including cortex, striatum, cerebellum, and hippocampus. A growing body of evidence suggests that aberrant D3R signaling contributes to multiple brain diseases, such as Parkinson's disease, essential tremor, schizophrenia, and addiction. In line with these findings, D3R has emerged as a potential target in the treatment of neurological disorders. However, the mechanisms underlying neuronal D3R signaling are poorly understood, either in healthy or diseased brain...
2017: Journal of Central Nervous System Disease
https://www.readbyqxmd.com/read/28844595/cognitive-impairments-associated-with-alterations-in-synaptic-proteins-induced-by-the-genetic-loss-of-adenosine-a2a-receptors-in-mice
#2
Maria Moscoso-Castro, Marc López-Cano, Irene Gracia-Rubio, Francisco Ciruela, Olga Valverde
The study of psychiatric disorders usually focuses on emotional symptoms assessment. However, cognitive deficiencies frequently constitute the core symptoms, are often poorly controlled and handicap individual's quality of life. Adenosine receptors, through the control of both dopamine and glutamate systems, have been implicated in the pathophysiology of several psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder. Indeed, clinical data indicate that poorly responsive schizophrenia patients treated with adenosine adjuvants show improved treatment outcomes...
August 26, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28842709/the-parkinson-s-disease-associated-gpr37-receptor-interacts-with-striatal-adenosine-a2a-receptor-controlling-its-cell-surface-expression-and-function-in-vivo
#3
Xavier Morató, Rafael Luján, Marc López-Cano, Jorge Gandía, Igor Stagljar, Masahiko Watanabe, Rodrigo A Cunha, Víctor Fernández-Dueñas, Francisco Ciruela
G protein-coupled receptor 37 (GPR37) is an orphan receptor associated to Parkinson's disease (PD) neuropathology. Here, we identified GPR37 as an inhibitor of adenosine A2A receptor (A2AR) cell surface expression and function in vivo. In addition, we showed that GPR37 and A2AR do oligomerize in the striatum. Thus, a close proximity of GPR37 and A2AR at the postsynaptic level of striatal synapses was observed by double-labelling post-embedding immunogold detection. Indeed, the direct receptor-receptor interaction was further substantiated by proximity ligation in situ assay...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28807491/adenosine-a2a-receptor-signaling-affects-il-21-il-22-cytokines-and-gata3-t-bet-transcription-factor-expression-in-cd4-t-cells-from-a-btbr-t-itpr3tf-j-mouse-model-of-autism
#4
Sheikh F Ahmad, Mushtaq A Ansari, Ahmed Nadeem, Saleh A Bakheet, Mashal M Almutairi, Sabry M Attia
Autism is a complex heterogeneous neurodevelopmental disorder; previous studies have identified altered immune responses among individuals diagnosed with autism. An imbalance in the production of pro- and anti-inflammatory cytokines and transcription factors plays a role in neurodevelopmental behavioral and autism disorders. BTBR T(+) Itpr3tf/J (BTBR) mice are used as a model for autism, as they exhibit social deficits, communication deficits, and repetitive behaviors compared with C57BL/6J (B6) mice. The adenosine A2A receptor (A2AR) appears to be a potential target for the improvement of behavioral, inflammatory, immune, and neurological disorders...
August 9, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28779842/strategy-for-the-thermostabilization-of-an-agonist-bound-gpcr-coupled-to-a-g-protein
#5
Annette Strege, Byron Carpenter, Patricia C Edwards, Christopher G Tate
Structure determination of G protein-coupled receptors (GPCRs) in the inactive state bound to high-affinity antagonists has been very successful through the implementation of a number of protein engineering and crystallization strategies. However, the structure determination of GPCRs in their fully active state coupled to a G protein is still very challenging. Recently, mini-G proteins were developed, which recapitulate the coupling of a full heterotrimeric G protein to a GPCR despite being less than one-third of the size...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28774332/baicalin-attenuates-chronic-hypoxia-induced-pulmonary-hypertension-via-adenosine-a2a-receptor-induced-sdf-1-cxcr4-pi3k-akt-signaling
#6
Xiaoying Huang, Peiliang Wu, Feifei Huang, Min Xu, Mayun Chen, Kate Huang, Guo-Ping Li, Manhuan Xu, Dan Yao, Liangxing Wang
BACKGROUND: Baicalin, an important flavonoid in Scutellaria baicalensis Georgi extracts, exerts a variety of pharmacological effects. In this study, we explored the effects of baicalin on chronic hypoxia-induced pulmonary arterial hypertension (PAH) and investigated the mechanism underlying these effects. Moreover, we examined whether the inflammatory response was mediated by the A2A receptor (A2AR) and stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-induced phosphatidyl inositol-3-kinase (PI3K) signaling in vivo...
August 3, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28758541/cobra-neurotoxin-produces-central-analgesic-and-hyperalgesic-actions-via-adenosine-a1-and-a2a-receptors
#7
Chuang Zhao, Jun Zhao, Qian Yang, Yong Ye
Cobra neurotoxin, a short-chain peptide isolated from snake venom of Naja naja atra, showed both a central analgesic effect and a hyperalgesic effect in mice tests. In order to explore mechanisms, a hypothesis is put forward that cobra neurotoxin takes effect through adenosine receptor pathway. The central effects of cobra neurotoxin were evaluated using the hot plate test (a model of acute pain) and the spinal cord injury (a model of central pain) in mice and using A1 receptor antagonist (DPCPX) and A2A receptor antagonist (ZM241385); behaviors were scored and signal molecules such as reactive oxygen species and adenosine triphosphate levels and mitogen-activated protein kinases/extracellular signal-regulated protein kinase expression were measured...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28712806/structures-of-human-a1-and-a2a-adenosine-receptors-with-xanthines-reveal-determinants-of-selectivity
#8
Robert K Y Cheng, Elena Segala, Nathan Robertson, Francesca Deflorian, Andrew S Doré, James C Errey, Cédric Fiez-Vandal, Fiona H Marshall, Robert M Cooke
The adenosine A1 and A2A receptors belong to the purinergic family of G protein-coupled receptors, and regulate diverse functions of the cardiovascular, respiratory, renal, inflammation, and CNS. Xanthines such as caffeine and theophylline are weak, non-selective antagonists of adenosine receptors. Here we report the structure of a thermostabilized human A1 receptor at 3.3 Å resolution with PSB36, an A1-selective xanthine-based antagonist. This is compared with structures of the A2A receptor with PSB36 (2...
August 1, 2017: Structure
https://www.readbyqxmd.com/read/28668513/toll-like-receptors-nf-%C3%AE%C2%BAb-and-il-27-mediate-adenosine-a2a-receptor-signaling-in-btbr-t-itpr3-tf-j-mice
#9
Sheikh F Ahmad, Mushtaq A Ansari, Ahmed Nadeem, Saleh A Bakheet, Laila Yousef Al-Ayadhi, Sabry M Attia
Autism is a predominant neurodevelopmental disorder characterized by impaired communication, social deficits, and repetitive behaviors. Recent research has proposed that the impairment of innate immunity may play an important role in autism. Toll-like receptors (TLRs) are potential therapeutic targets against neuroinflammation. The BTBR T(+) Itpr3(tf/)J (BTBR) mouse is a well-known model of autism, showing repetitive behaviors such as cognitive inflexibility and increased grooming as compared to C57BL/6 (B6) mice...
June 29, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28667836/adenosine-a2a-receptor-blockade-diminishes-wnt-%C3%AE-catenin-signaling-in-a-murine-model-of-bleomycin-induced-dermal-fibrosis
#10
Jin Zhang, Carmen Corciulo, Hailing Liu, Tuere Wilder, Mayumi Ito, Bruce Cronstein
Adenosine A2a receptor (A2aR) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A2aR and WNT/β-catenin signaling pathway. In in vitro studies, A2aR signaling for collagen III expression was mediated by WNT/β-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A2aR and Wnt/β-catenin signaling was involved in diffuse dermal fibrosis in vivo. Wnt-signaling reporter mice (Tcf/Lef:H2B-GFP) were challenged with bleomycin and treated with the selective A2aR antagonist istradefylline (KW6002) or vehicle...
September 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28661196/design-synthesis-and-evaluation-of-2-aryl-benzoxazoles-as-promising-hit-for-the-a2a-receptor
#11
Romain Duroux, Nicolas Renault, Joana Esteves Cuelho, Laurence Agouridas, David Blum, Luisa V Lopes, Patricia Melnyk, Saïd Yous
The development of adenosine A2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A2A receptor. Compound F1, with an affinity of 1 μm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184 μm) without being cytotoxic at 100 μm...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28660236/expression-purification-and-crystallisation-of-the-adenosine-a2a-receptor-bound-to-an-engineered-mini-g-protein
#12
Byron Carpenter, Christopher G Tate
G protein-coupled receptors (GPCRs) promote cytoplasmic signalling by activating heterotrimeric G proteins in response to extracellular stimuli such as light, hormones and nucleosides. Structure determination of GPCR-G protein complexes is central to understanding the precise mechanism of signal transduction. However, these complexes are challenging targets for structural studies due to their conformationally dynamic and inherently transient nature. We recently developed an engineered G protein, mini-Gs, which addressed these problems and allowed the formation of a stable GPCR-G protein complex...
April 20, 2017: Bio-protocol
https://www.readbyqxmd.com/read/28652244/targeting-adenosine-in-braf-mutant-melanoma-reduces-tumor-growth-and-metastasis
#13
Arabella Young, Shin Foong Ngiow, Jason Madore, Julia Reinhardt, Jennifer Landsberg, Arash Chitsazan, Jai Rautela, Tobias Bald, Deborah S Barkauskas, Elizabeth Ahern, Nicholas D Huntington, Dirk Schadendorf, Georgina V Long, Glen M Boyle, Michael Hölzel, Richard A Scolyer, Mark J Smyth
Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAF(V600E) melanoma. In AJCC stage III melanoma patients, CD73 expression (the enzyme that generates adenosine) correlated significantly with patients presenting nodal metastatic melanoma, suggesting that targeting this pathway may be effective in advanced stage disease...
June 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28638737/selective-activation-of-anti-cd73-mechanisms-in-control-of-primary-tumors-and-metastases
#14
Dipti Vijayan, Deborah S Barkauskas, Kimberley Stannard, Erin Sult, Rebecca Buonpane, Kazuyoshi Takeda, Michele W L Teng, Kris Sachsenmeier, Carl Hay, Mark J Smyth
The emerging role for CD73 in driving cancer growth and metastasis has presented opportunities to develop anti-CD73 monoclonal antibodies (mAbs) in the treatment of human cancers. Blockade of CD73 by antagonistic CD73 mAbs ameliorates tumor growth and metastasis via the inhibition of enzymatic and non-enzymatic CD73 pathways. In this study, we investigated whether Fc-receptor cross-linking represented a non-redundant mechanism by which anti-CD73 mAbs exert potent suppression of solid tumors and metastases. We engineered four anti-CD73 mAbs, each different in their ability to modulate CD73 enzymatic function and bind Fc receptors...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28629145/synthesis-and-evaluation-of-phenylxanthine-derivatives-as-potential-dual-a2ar-antagonists-mao-b-inhibitors-for-parkinson-s-disease
#15
Xuebao Wang, Chao Han, Yong Xu, Kaiqi Wu, Shuangya Chen, Mangsha Hu, Luyao Wang, Yun Ye, Faqing Ye
The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson's disease. To explore this hypothesis, two series of PX derivatives were prepared and their antagonism against A2AR and inhibition against MAO-B were determined in vitro. In order to evaluate further the antiparkinsonian properties, pharmacokinetic and haloperidol-induced catalepsy experiments were carried out in vivo...
June 17, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28612530/-minocycline-prevent-microglial-activation-via-suppression-of-adenosine-a-2a-receptor-in-a-rat-stroke-ischemia-reperfusion-model
#16
Tao Tao, Jie Fu, Yong-Gang Liu, Zuo-Xiao Li, Xiao-Gang Li
OBJECTIVES: To investigate whether minocycline could inhibit neuroinflammation induced by microglia activation through suppression of adenosine A2Areceptor (A2AR)expression in rats after cerebral ischemia/reperfusion (I/R) injury. METHODS: Thirty male Sprageue-Dawley rats were randomly divided into 3 groups: sham group, I/R group and minocycline group. The rats were subjected to occlusion of the right middle cerebral artery (MCAO) for 2 h to establish stroke I/R model, and 3 mg/kg minocycline was injected intravenously immediately after reperfusion twice a day in minocycline group...
March 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28592285/blockade-of-adenosine-a2a-receptor-enhances-cd8-t-cells-response-and-decreases-regulatory-t-cells-in-head-and-neck-squamous-cell-carcinoma
#17
Si-Rui Ma, Wei-Wei Deng, Jian-Feng Liu, Liang Mao, Guang-Tao Yu, Lin-Lin Bu, Ashok B Kulkarni, Wen-Feng Zhang, Zhi-Jun Sun
BACKGROUND: Cancer immunotherapy offers a promising approach in cancer treatment. The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. To date, the role of A2AR in head and neck squamous cell carcinoma (HNSCC) has not been investigated. Here, we sought to explore the expression and immunotherapeutic value of A2AR blockade in HNSCC. METHODS: The expression of A2AR was evaluated by immunostaining in 43 normal mucosae, 48 dysplasia and 165 primary HNSCC tissues...
June 7, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28583881/altered-adenosine-2a-and-dopamine-d2-receptor-availability-in-the-6-hydroxydopamine-treated-rats-with-and-without-levodopa-induced-dyskinesia
#18
X Zhou, J Doorduin, P H Elsinga, R A J O Dierckx, E F J de Vries, C Casteels
Several lines of evidence imply alterations in adenosine signaling in Parkinson's disease (PD). Here, we investigated cerebral changes in adenosine 2A receptor (A2AR) availability in 6-hydroxydopamine (6-OHDA)-lesioned rats with and without levodopa-induced dyskinesia (LID) using positron-emission tomography (PET) with [(11)C]preladenant. In parallel dopamine type 2 receptor (D2R) imaging with [(11)C]raclopride PET and behavioral tests for motor and cognitive function were performed. METHODS: Parametric A2AR and D2R binding potential (BPND) images were reconstructed using reference tissue models with midbrain and cerebellum as reference tissue, respectively...
June 2, 2017: NeuroImage
https://www.readbyqxmd.com/read/28582704/a-novel-antagonist-of-the-immune-checkpoint-protein-adenosine-a2a-receptor-restores-tumor-infiltrating-lymphocyte-activity-in-the-context-of-the-tumor-microenvironment
#19
Melanie Mediavilla-Varela, Julio Castro, Alberto Chiappori, David Noyes, Dalia C Hernandez, John Stagg, Scott J Antonia
BACKGROUND: Therapeutic strategies targeting immune checkpoint proteins have led to significant responses in patients with various tumor types. The success of these studies has led to the development of various antibodies/inhibitors for the different checkpoint proteins involved in immune evasion of the tumor. Adenosine present in high concentrations in the tumor microenvironment activates the immune checkpoint adenosine A2a receptor (A2aR), leading to the suppression of antitumor responses...
June 2, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28554302/new-cardiac-expression-of-two-adenosine-2a-receptor-isoforms-in-dysfunctioning-minipigs
#20
Manuela Cabiati, Benedetta Svezia, Marco Matteucci, Luca Panchetti, Silvia Burchielli, Maria-Aurora Morales, Silvia Del Ry
PURPOSE: Eight A2AR variants are reported in humans while no A2AR isoforms in pigs. The aim of this study was to evaluate potential isoforms presence in cardiac pig tissue to better define possible involvement of A2AR in the cardiovascular pathophysiology. MATERIALS AND METHODS: In adult male minipigs (n = 4) left ventricular dysfunction (LVD) was induced by pacing at 200 bpm in the right ventricular (RV) apex. In these animals and in sham operated pigs (C-SHAM, n = 4) cardiac tissue was collected from LV-septal wall (LV-SW)-close to pacing site-and from lateral (opposite) site (LV-OSW)...
August 2017: Journal of Receptor and Signal Transduction Research
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