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.
Highlights
Intracellular free nucleotides originate mainly in the liver through de novo synthesis pathways [1]
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
As for many other compounds, liver synthesizes nucleotides for exportation, and, since de novo synthesis produces phosphorylated compounds, they must be dephosphorylated into nucleosides and in part phosphorolytically cleaved into bases and ribose-1-phosphate (Rib-1-P), in order to leave the hepatocyte, enter the blood flux, and be taken up by cells and organs in the body
Summary
Intracellular free nucleotides originate mainly in the liver through de novo synthesis pathways [1]. At low energy charge, AMP can accumulate inside the cell at high micromolar concentrations, activating a specific AMP-dependent protein kinase (AMPK), the master regulator of cellular energy homeostasis [6]. It can be dephosphorylated by a high KM AMP specific 5 -nucleotidase I (cN-I), which is strongly activated by ADP, leading to Ado accumulation inside the cell [7]. The authors conclude that hypothermia induced by Ado in mice is a combined response to a receptor-mediated (mainly A1-mediated) mechanism and to a still-unknown intracellular mechanism in which AdoK plays a fundamental regulatory role [24]
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