Metabolic Aspects of Adenosine Functions in the Brain

Abstract

Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5'-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington's disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.

Keywords: 5′-nucleotidases; S-adenosylhomocysteine hydrolase; adenosine; adenosine deaminase; adenosine kinase; brain; metabolism; nucleoside transporters.

FIGURE 1

Extra- and intracellular adenosine production. Extracellularly, ATP can be dephosphorylated to AMP by ectonucleoside triphosphate diphospho-hydrolase (CD39) or ecto-nucleotide pyrophosphatase/phosphodiesterase. Then, AMP can be dephosphorylated to adenosine by the extracellular 5′-nucleotidase, CD73. Extracellular adenosine can be converted into hypoxanthine (Hyp) and ribose-1 phosphate (Rib-1-P) by the combined action of ectosolic adenosine deaminase and purine nucleoside phosphorylase. Extracellular Rib-1-P might be dephosphorylated by membrane phosphatases and equilibrates with the intracellular ribose through a not yet defined transporter (?). Inside the cell, at low energy charge, adenosine originates mainly from AMP and can be exported or deaminated. When extracellular adenosine generated from ATP breakdown is transported inside the cell, it might be phosphorylated by the low K_M ADK or deaminated by the high K_M ADA if adenosine reaches high levels. 1,3: ecto-nucleoside triphosphate diphosphohydrolase; 2: ecto-nucleotide pyrophosphatase/phosphodiesterase; 4: ecto-5′-nucleotidase; 5: adenosine deaminase; 6: purine nucleoside phosphorylase; 7: ribokinase; 8: phosphoribomutase; 9: 5-phosphoribosyl-1-pyrophosphate synthetase; 10: hypoxanthine guanine phosphoribosyltransferase; 11: adenosine kinase; 12: cytosolic 5′ nucleotidase I; 13: AMP deaminase; 14: cytosolic 5′ nucleotidase II; 15: S-adenosylhomocysteine hydrolase. Ado: adenosine; CNT: concentrative nucleoside transporter; ENT: equilibrative nucleoside transporter; Hyp: hypoxanthine; Ino: inosine; P1: purinergic receptor type 1; P2: purinerigic receptor type 2; Rib-1-P: ribose-1-phosphate; Rib-5-P: ribose-5-phosphate. Green and orange boxes indicate that these pathways are described in more details in Figures 2, 3. +: stimulation; -: inhibition.

FIGURE 2

Purine nucleotide cycles. 1: 5′-nucleotidase I; 2: adenosine kinase; 3: AMP deaminase; 4: adenylosuccinate synthase; 5: adenylosuccinate lyase; 6: cytosolic 5′-nucleotidase II; 7: adenosine deaminase; 8: IMP dehydrogenase; 9: GMP synthase; 10: purine nucleoside phosphorylase; 11: hypoxanthine guanine phosphoribosyltransferase. The figure also shows that AMP is an activator of AMP-activated protein kinase (AMPK). Ado: adenosine; Gua: guanine; Guo: guanosine; Hyp: hypoxhanthine; Ino: inosine. S-AMP: succinylAMP. +: stimulation.

FIGURE 3

Relationship between adenosine, ADK and transmethylation reactions in subcellular compartments. In the transmethylation reactions catalyzed by methyltransferases (MT), S-adenosylmethionine (SAM) donates the methyl group to various acceptors and is converted to S-adenosylhomocysteine (SAH), which generates adenosine (Ado) by the action of S-adenosylhomocysteine hydrolase (SAHH). In the nucleus, the methyl group can be transferred to DNA and histones. The activity of ADK (ADK_S in the cytoplasm and ADK_L in the nucleus) decreases the concentration of Ado and favors the transmethylation reactions. In this way, ADK_L contributes to the DNA methylation in the nucleus.