Ecto-5’-Nucleotidase (Nt5e/CD73)-Mediated Adenosine Signaling Attenuates TGFβ-2 Induced Elastin and Cellular Contraction
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE216727 | GEO | 2022/11/01
REPOSITORIES: GEO
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Project description:Ecto-5’-Nucleotidase (Nt5e/CD73)-Mediated Adenosine Signaling Attenuates TGFβ-2 Induced Elastin and Cellular Contraction
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Project description:Ecto-5'-nucleotidase (NT5E, CD73) is a membrane-anchored protein that hydrolyzes extracellular adenosine 5'-monophosphate (AMP) to adenosine in diverse tissues but has not been directly studied in nociceptive neurons. We found that NT5E was located on peptidergic and nonpeptidergic nociceptive neurons in dorsal root ganglia (DRG) and on axon terminals in lamina II (the substantia gelatinosa) of spinal cord. NT5E was also located on epidermal keratinocytes, cells of the dermis, and on nociceptive axon terminals in the epidermis. Following nerve injury, NT5E protein and AMP histochemical staining were coordinately reduced in lamina II. In addition, AMP hydrolytic activity was reduced in DRG neurons and spinal cord of Nt5e(-/-) mice. The antinociceptive effects of AMP, when combined with the adenosine kinase inhibitor 5-iodotubericidin, were reduced by approximately 50% in Nt5e(-/-) mice and were eliminated in Adenosine A(1) receptor (A(1)R, Adora1) knock-out mice. Additionally, Nt5e(-/-) mice displayed enhanced sensitivity in the tail immersion assay, in the complete Freund's adjuvant model of inflammatory pain and in the spared nerve injury model of neuropathic pain. Collectively, our data indicate that the ectonucleotidase NT5E regulates nociception by hydrolyzing AMP to adenosine in nociceptive circuits and represents a new molecular target for the treatment of chronic pain. Moreover, our data suggest NT5E is well localized to regulate nucleotide signaling between skin cells and sensory axons.
| S-EPMC2826808 | biostudies-literature
Project description:Ecto-5'-nucleotidase (CD73) catalyzes the hydrolysis of AMP to anti-inflammatory, immunosuppressive adenosine. It is expressed on vascular endothelial, epithelial, and also numerous cancer cells where it strongly contributes to an immunosuppressive microenvironment. In the present study we designed and synthesized fluorescent-labeled CD73 inhibitors with low nanomolar affinity and high selectivity based on N 6 -benzyl-α,β-methylene-ADP (PSB-12379) as a lead structure. Fluorescein was attached to the benzyl residue via different linkers resulting in PSB-19416 (14b, K i 12.6 nM) and PSB-18332 (14a, K i 2.98 nM) as fluorescent high-affinity probes for CD73. These compounds are anticipated to become useful tools for biological studies, drug screening, and diagnostic applications.
| S-EPMC7667873 | biostudies-literature
Project description:Purinergic signaling is a fundamental mechanism used by all cells to control their internal activities and interact with the environment. A key component of the purinergic system, the enzyme ecto-5'-nucleotidase (CD73) catalyzes the last step in the extracellular metabolism of ATP to form adenosine. Efforts to harness the therapeutic potential of endogenous adenosine in cancer have culminated in the ongoing clinical development of multiple CD73-targeting antibodies and small-molecule inhibitors. However, recent studies are painting an increasingly complex picture of CD73 mRNA and protein regulation and function in cellular homeostasis, physiological adaptation, and disease development. This review discusses the latest conceptual and methodological advances that are helping to unravel the complexity of this important enzyme that was identified nearly 90 years ago.
| S-EPMC8448938 | biostudies-literature
Project description:BackgroundAdenosine is a powerful trigger for ischemic preconditioning (IPC). Myocardial ischemia induces intracellular and extracellular ATP degradation to adenosine, which then activates adenosine receptors and elicits cardioprotection. Conventionally extracellular adenosine formation by ecto-5'-nucleotidase (CD73) during ischemia was thought to be negligible compared to the massive intracellular production, but controversial reports in the past demand further evaluation. In this study we evaluated the relevance of ecto-5'-nucleotidase (CD73) for infarct size reduction by ischemic preconditioning in in vitro and in vivo mouse models of myocardial infarction, comparing CD73-/- and wild type (WT) mice.Methods and results3x5 minutes of IPC induced equal cardioprotection in isolated saline perfused hearts of wild type (WT) and CD73-/- mice, reducing control infarct sizes after 20 minutes of ischemia and 90 minutes of reperfusion from 46 ± 6.3% (WT) and 56.1 ± 7.6% (CD73-/-) to 26.8 ± 4.7% (WT) and 25.6 ± 4.7% (CD73-/-). Coronary venous adenosine levels measured after IPC stimuli by high-pressure liquid chromatography showed no differences between WT and CD73-/- hearts. Pharmacological preconditioning of WT hearts with adenosine, given at the measured venous concentration, was evenly cardioprotective as conventional IPC. In vivo, 4x5 minutes of IPC reduced control infarct sizes of 45.3 ± 8.9% (WT) and 40.5 ± 8% (CD73-/-) to 26.3 ± 8% (WT) and 22.6 ± 6.6% (CD73-/-) respectively, eliciting again equal cardioprotection. The extent of IPC-induced cardioprotection in male and female mice was identical.ConclusionThe infarct size limiting effects of IPC in the mouse heart in vitro and in vivo are not significantly affected by genetic inactivation of CD73. The ecto-5'-nucleotidase derived extracellular formation of adenosine does not contribute substantially to adenosine's well known cardioprotective effect in early phase ischemic preconditioning.
| S-EPMC4532361 | biostudies-literature
Project description:BackgroundEcto-5'-nucleotidase (NT5E, also known as CD73) hydrolyzes extracellular adenosine 5'-monophosphate (AMP) to adenosine in nociceptive circuits. Since adenosine has antinociceptive effects in rodents and humans, we hypothesized that NT5E, an enzyme that generates adenosine, might also have antinociceptive effects in vivo.ResultsTo test this hypothesis, we purified a soluble version of mouse NT5E (mNT5E) using the baculovirus expression system. Recombinant mNT5E hydrolyzed AMP in biochemical assays and was inhibited by alpha,beta-methylene-adenosine 5'-diphosphate (alpha,beta-me-ADP; IC50 = 0.43 microM), a selective inhibitor of NT5E. mNT5E exhibited a dose-dependent thermal antinociceptive effect that lasted for two days when injected intrathecally in wild-type mice. In addition, mNT5E had thermal antihyperalgesic and mechanical antiallodynic effects that lasted for two days in the complete Freund's adjuvant (CFA) model of inflammatory pain and the spared nerve injury (SNI) model of neuropathic pain. In contrast, mNT5E had no antinociceptive effects when injected intrathecally into adenosine A1 receptor (A1R, Adora1) knockout mice.ConclusionOur data indicate that the long lasting antinociceptive effects of mNT5E are due to hydrolysis of AMP followed by activation of A1R. Moreover, our data suggest recombinant NT5E could be used to treat chronic pain and to study many other physiological processes that are regulated by NT5E.
| S-EPMC2874211 | biostudies-literature
Project description:Nucleotides and nucleosides influence nearly every aspect of physiology and pathophysiology. Extracellular nucleotides are metabolized through regulated phosphohydrolysis by a series of ecto-nucleotidases. The formation of extracellular adenosine from adenosine 5'-monophosphate is accomplished primarily through ecto-5'-nucleotidase (CD73), a glycosyl phosphatidylinositol-linked membrane protein found on the surface of a variety of cell types. Recent in vivo studies implicating CD73 in a number of tissue protective mechanisms have provided new insight into its regulation and function and have generated considerable interest. Here, we review contributions of CD73 to cell and tissue stress responses, with a particular emphasis on physiologic responses to regulated CD73 expression and function, as well as new findings utilizing Cd73-deficient animals.
| S-EPMC2254482 | biostudies-other