The Inside Story of Adenosine

Abstract

Several physiological functions of adenosine (Ado) appear to be mediated by four G protein-coupled Ado receptors. Ado is produced extracellularly from the catabolism of the excreted ATP, or intracellularly from AMP, and then released through its transporter. High level of intracellular Ado occurs only at low energy charge, as an intermediate of ATP breakdown, leading to hypoxanthine production. AMP, the direct precursor of Ado, is now considered as an important stress signal inside cell triggering metabolic regulation through activation of a specific AMP-dependent protein kinase. Intracellular Ado produced from AMP by allosterically regulated nucleotidases can be regarded as a stress signal as well. To study the receptor-independent effects of Ado, several experimental approaches have been proposed, such as inhibition or silencing of key enzymes of Ado metabolism, knockdown of Ado receptors in animals, the use of antagonists, or cell treatment with deoxyadenosine, which is substrate of the enzymes acting on Ado, but is unable to interact with Ado receptors. In this way, it was demonstrated that, among other functions, intracellular Ado modulates angiogenesis by regulating promoter methylation, induces hypothermia, promotes apoptosis in sympathetic neurons, and, in the case of oxygen and glucose deprivation, exerts a cytoprotective effect by replenishing the ATP pool.

Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway

“…It has been reported that intracellular adenosine could be converted to other metabolites, including AMP and inosine. Adenosine could be phosphorylated to AMP by the activity of adenosine kinase, or it could be converted to inosine by the activity of adenosine deaminase as mentioned previously [41]. Accordingly, the potential metabolic change of adenosine in adenosine-mediated CCA cell suppression was elucidated.…”

“…Therefore, we further investigated the possible metabolic phases of adenosine once it was transported into CCA cells. In normal cells, intracellular adenosine could be converted to AMP by the activity of adenosine kinase to regenerate the energy carrier molecules (ADP and ATP, subsequently) and to serve as a precursor for nucleotide synthesis [41]. On the other hand, adenosine could also be deaminated by adenosine deaminase to inosine, which can also be used as another precursor in nucleotide synthesis [41].…”

“…In normal cells, intracellular adenosine could be converted to AMP by the activity of adenosine kinase to regenerate the energy carrier molecules (ADP and ATP, subsequently) and to serve as a precursor for nucleotide synthesis [41]. On the other hand, adenosine could also be deaminated by adenosine deaminase to inosine, which can also be used as another precursor in nucleotide synthesis [41]. Hence, to validate the roles of adenosine kinase, metabolic stable adenosine (2Cl-adenosine) and inosine were further tested to elucidate the potential metabolic phases of intrasellar adenosine in adenosine-treated CCA cells.…”

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

“…Extracellular adenosine is considered a retaliatory metabolite in a protective feedback control pathway in response to excessive intracellular ATP consumption (Newby 1984). Intracellular AMP and adenosine rise when ATP is depleted in low energy states and function as metabolic stress signals, leading to activation of non-AR-dependent mechanisms such as AMP-dependent protein kinase (AMPK) (Camici et al, 2018) and, indirectly, to AR activation by extracellular adenosine. Extracellular adenosine can also be produced locally during injury or an inflammatory response (Haskó et al, 2008).…”

Efeito do óxido nítrico sobre a atividade e expressão da ntpdase1 e da ecto-5'-nucleotidase em linhagens de células vasculares

“…Adenosine is of great importance to ensure the regulation of homeostasis and maintenance of vascular tonus [34]. Higher concentrations of adenosine may also be considered as a stressful condition and the signal causes adenosine phosphorylation to AMP by the low KM of adenosine kinase, consequently increasing the activity of ecto-5 '-nucleotidase [35], reinforcing the feedback regulation.…”