The adenosine metabolite inosine is a functional agonist of the adenosine A2A receptor with a unique signaling bias
| Autor: | Yongjiao Zhai, Ajith Welihinda, Edward P. Amento, Manmeet Kaur, Kelly Greene |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adenosine A2 Receptor Agonists Drug Inverse Agonism Receptor Adenosine A2A Adenosine A2A receptor Purine nucleoside phosphorylase CHO Cells Article Mice 03 medical and health sciences chemistry.chemical_compound Cricetulus 0302 clinical medicine Cricetinae Cyclic AMP medicine Animals Humans Extracellular Signal-Regulated MAP Kinases Inosine CGS-21680 Dose-Response Relationship Drug Chemistry Cell Biology Adenosine receptor Adenosine Cell biology 030104 developmental biology Biochemistry Nucleoside 030217 neurology & neurosurgery Adenosine A2B receptor Signal Transduction medicine.drug |
| Zdroj: | Cellular Signalling. 28:552-560 |
| ISSN: | 0898-6568 |
| Popis: | Inosine is an endogenous purine nucleoside that is produced by catabolism of adenosine. Adenosine has a short half-life (approximately 10 s) and is rapidly deaminated to inosine, a stable metabolite with a half-life of approximately 15 h. Resembling adenosine, inosine acting through adenosine receptors (ARs) exerts a wide range of anti-inflammatory and immunomodulatory effects in vivo. The immunomodulatory effects of inosine in vivo, at least in part, are mediated via the adenosine A2A receptor (A2AR), an observation that cannot be explained fully by in vitro pharmacological characterization of inosine at the A2AR. It is unclear whether the in vivo effects of inosine are due to inosine or a metabolite of inosine engaging the A2AR. Here, utilizing a combination of label-free, cell-based, and membrane-based functional assays in conjunction with an equilibrium agonist-binding assay we provide evidence for inosine engagement at the A2AR and subsequent activation of downstream signaling events. Inosine-mediated A2AR activation leads to cAMP production with an EC50 of 300.7 μM and to extracellular signal-regulated kinase-1 and -2 (ERK1/2) phosphorylation with an EC50 of 89.38 μM. Our data demonstrate that inosine produces ERKl/2-biased signaling whereas adenosine produces cAMP-biased signaling at the A2AR, highlighting pharmacological differences between these two agonists. Given the in vivo stability of inosine, our data suggest an additional, previously unrecognized, mechanism that utilizes inosine to functionally amplify and prolong A2AR activation in vivo. |
| Databáze: | OpenAIRE |
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