Allosteric modulators of human A2B adenosine receptor

Trincavelli, Maria Letizia; Giacomelli, Chiara; Daniele, Simona; Taliani, Sabrina; Cosimelli, Barbara; Laneri, Sonia; Severi, Elda; Barresi, Elisabetta; Pugliesi, Isabella; Greco, Giovanni; Novellino, Ettore; Settimo, Federico Da; Martini, Claudia

doi:10.1016/j.bbagen.2013.12.021

Cited by 27 publications

(27 citation statements)

References 47 publications

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“…17 In this work, we also found that A 2B AR agonists at lower concentration than 0.1 or 1 mM are unable to obviously stimulate the tube formation in vitro. Therefore, the A 2B AR represents a potential target for pharmacological repair of damaged tissues.…”

Section: Discussionmentioning

confidence: 50%

Adenosine A_2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells

Song

et al. 2015

Exp Biol Med (Maywood)

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Angiogenesis is critical to wound repair due to its role in providing oxygen and nutrients that are required to support the growth and function of reparative cells in damaged tissues. Adenosine receptors are claimed to be of paramount importance in driving wound angiogenesis by inducing VEGF. However, the underlying mechanisms for the regulation of adenosine receptors in VEGF as well as eNOS remain poorly understood. In the present study, we found that adenosine and the non-selective adenosine receptor agonists (NECA) induced tube formation in HMEC-1 in a dose-dependent manner. Adenosine or NECA (10 mmol/L) significantly augmented the number and length of the segments in comparison with the control. Simultaneously, VEGF and eNOS were significantly upregulated following the administration of 10 mmol/L NECA, while they were suppressed after A 2B AR genetic silencing and pharmacological inhibition by MRS1754. In addition, VEGF expression and eNOS bioavailability elimination significantly reduced the formation of capillary-like structures. Furthermore, the activation of A 2B AR by NECA significantly increased the intracellular cAMP levels and concomitant CREB phosphorylation, eventually leading to the production of VEGF in HMEC-1. However, the activated PKA-CREB pathway seemed to be invalidated in the induction of eNOS. Moreover, we found that the elicited PI3K/AKT signaling in response to the induction of NECA assisted in regulating eNOS but failed to impact on VEGF generation. In conclusion, the A 2B AR activation-driven angiogenesis via cAMP-PKA-CREB mediated VEGF production and PI3K/ AKT-dependent upregulation of eNOS in HMEC-1.

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Section: Discussionmentioning

confidence: 50%

Adenosine A_2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells

Song

et al. 2015

Exp Biol Med (Maywood)

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“…At each time of differentiation, cells were stimulated with BAY60-6583 (5 nM) for 15 min and cAMP levels were quantified. In the desensitization assays, MSCs (differentiated for 0, 5, or 15 days in the absence or presence of TNF-␣) were pretreated with BAY60-6583 (5 nM) for different times (5 to 120 min) and then washed and stimulated with BAY60-6583 (5 nM) for 15 min in the presence of 1 U/ml of adenosine deaminase (ADA) and the phosphodiesterase inhibitor Ro 20-1724 (20 M) (56). At the end of treatments, intracellular cAMP levels were quantified using a competitive protein binding method (57).…”

Section: Figmentioning

confidence: 99%

Osteogenesis Is Improved by Low Tumor Necrosis Factor Alpha Concentration through the Modulation of Gs-Coupled Receptor Signals

Daniele

Natali

Giacomelli

et al. 2017

Molecular and Cellular Biology

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In the early phase of bone damage, low concentrations of the cytokine tumor necrosis factor alpha (TNF-α) favor osteoblast differentiation. In contrast, chronic high doses of the same cytokine contribute to bone loss, demonstrating opposite effects depending on its concentration and on the time of exposure. In the bone microenvironment, TNF-α modulates the expression/function of different G protein-coupled receptors (GPCRs) and of their regulatory proteins, GPCR-regulated kinases (GRKs), thus dictating their final biological outcome in controlling bone anabolic processes. Here, the effects of TNF-α were investigated on the expression/responsiveness of the A adenosine receptor (AAR), a Gs-coupled receptor that promotes mesenchymal stem cell (MSC) differentiation into osteoblasts. Low TNF-α concentrations exerted a prodifferentiating effect on MSCs, pushing them toward an osteoblast phenotype. By regulating GRK2 turnover and expression, the cytokine impaired AAR desensitization, accelerating receptor-mediated osteoblast differentiation. These data supported the anabolic effect of TNF-α submaximal concentration and demonstrated that the cytokine regulates GPCR responses by interfering with the receptor desensitization machinery, thereby enhancing the anabolic responses evoked by AAR ligands. Overall, these results indicated that GPCR desensitization plays a pivotal role in osteogenesis and that its manipulation is an effective strategy to favor bone remodeling.

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“…A 2B R are the least well‐characterized subtype of ARs, mainly due to the lack of suitable specific ligands . However, selective agonists and selective antagonists are now commercially available . These receptors have low affinity for adenosine and are expressed at low levels in the brain and at high levels in the kidney, gastrointestinal tract, urinary bladder, lung, and various immune cells .…”

Section: Cell Surface Ada As An Allosteric Modulator Of Arsmentioning

confidence: 99%

“…The A 2B R antagonist GS‐6201 has been shown to be therapeutically beneficial in the treatment of experimental pulmonary fibrosis and, in 2012, studies by Karmouty‐Quintana et al supported the development of A 2B R antagonists for the treatment of pulmonary hypertension associated with interstitial lung disease. Finally, the potent and selective A 2B R agonist BAY 60–6583 is currently being investigated for the treatment of atherosclerosis and coronary artery disorders …”

Section: Cell Surface Ada As An Allosteric Modulator Of Arsmentioning

confidence: 99%

Moonlighting Adenosine Deaminase: A Target Protein for Drug Development

Cortés

Gracia

Moreno

et al. 2014

Medicinal Research Reviews

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Interest in adenosine deaminase (ADA) in the context of medicine has mainly focused on its enzymatic activity. This is justified by the importance of the reaction catalyzed by ADA not only for the intracellular purine metabolism, but also for the extracellular purine metabolism as well, because of its capacity as a regulator of the concentration of extracellular adenosine that is able to activate adenosine receptors (ARs). In recent years, other important roles have been described for ADA. One of these, with special relevance in immunology, is the capacity of ADA to act as a costimulator, promoting T-cell proliferation and differentiation mainly by interacting with the differentiation cluster CD26. Another role is the ability of ADA to act as an allosteric modulator of ARs. These receptors have very general physiological implications, particularly in the neurological system where they play an important role. Thus, ADA, being a single chain protein, performs more than one function, consistent with the definition of a moonlighting protein. Although ADA has never been associated with moonlighting proteins, here we consider ADA as an example of this family of multifunctional proteins. In this review, we discuss the different roles of ADA and their pathological implications. We propose a mechanism by which some of their moonlighting functions can be coordinated. We also suggest that drugs modulating ADA properties may act as modulators of the moonlighting functions of ADA, giving them additional potential medical interest.

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Allosteric modulators of human A2B adenosine receptor

Cited by 27 publications

References 47 publications

Adenosine A_2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells

Adenosine A_2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells

Osteogenesis Is Improved by Low Tumor Necrosis Factor Alpha Concentration through the Modulation of Gs-Coupled Receptor Signals

Moonlighting Adenosine Deaminase: A Target Protein for Drug Development

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Allosteric modulators of human A2B adenosine receptor

Cited by 27 publications

References 47 publications

Adenosine A2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells

Adenosine A2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells

Osteogenesis Is Improved by Low Tumor Necrosis Factor Alpha Concentration through the Modulation of Gs-Coupled Receptor Signals

Moonlighting Adenosine Deaminase: A Target Protein for Drug Development

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Adenosine A_2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells

Adenosine A_2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells