Adenosinergic System: Therapeutics for Drug Addiction
Adenosine is mainly derived from ATP via adenosine monophosphate (AMP) and various enzymatic reactions (Figure 3) and it exists in all cells of the body, including the neurons and glia. However, adenosine has a half-life in the order of seconds in physiological fluids, and its beneficial effects are, therefore, restricted to the tissue and cellular site where it is released. Adenosine does not accumulate in the synaptic vesicles, and therefore, the classical exocytotic release of neurotransmitters is not applied to the release of adenosine. Indeed, adenosine is released from the cytoplasm via nucleoside transporters, which also mediate adenosine reuptake, the direction of the transport being dependent upon the concentration gradient at both sides of the membrane.
(Enlarge Image)
Figure 3.
Diagrammatic representation of the intra- and extra-cellular pathways for the formation and metabolic regulation of adenosine.
ADA: Adenosine deaminase; AMP: Adenosine monophosphate; cAMP: Cyclic adenosine monophosphate; PDE: Phosphodiesterase; SAH: S-adenosyl homocysteine.
Basal adenosine levels in the extracellular fluid of healthy brains (sufficient to tonically activate a substantial fraction of high-affinity adenosine A1 and A2A receptors) is in the range of 25–250 nM. Reuptake of adenosine into the cell, followed by its intracellular metabolism, is responsible for the rapid disappearance of adenosine from the extracellular space.
Adenosine is maintained at this basal level by the following mechanisms:
The extracellular levels of adenosine are mostly regulated by cytosolic 5'-nucleotidase (converting AMP into adenosine) and adenosine, involved in the conversion of adenosine to AMP (Figure 3). Inhibition of adenosine kinase leads to an increase in extracellular adenosine levels owing to an enhancement of cytoplasmic adenosine concentration. An alternative pathway for the inactivation of extracellular adenosine is its metabolic transformation to inosine by ADA. During any insult to the brain, ADA assumes a prominent role in regulating extracellular adenosine concentrations. Under these conditions, the adenosine transporters are largely inactive, so ADA becomes important in the absence of any other mechanisms for adenosine removal.
Brain Adenosine Levels
Adenosine is mainly derived from ATP via adenosine monophosphate (AMP) and various enzymatic reactions (Figure 3) and it exists in all cells of the body, including the neurons and glia. However, adenosine has a half-life in the order of seconds in physiological fluids, and its beneficial effects are, therefore, restricted to the tissue and cellular site where it is released. Adenosine does not accumulate in the synaptic vesicles, and therefore, the classical exocytotic release of neurotransmitters is not applied to the release of adenosine. Indeed, adenosine is released from the cytoplasm via nucleoside transporters, which also mediate adenosine reuptake, the direction of the transport being dependent upon the concentration gradient at both sides of the membrane.
(Enlarge Image)
Figure 3.
Diagrammatic representation of the intra- and extra-cellular pathways for the formation and metabolic regulation of adenosine.
ADA: Adenosine deaminase; AMP: Adenosine monophosphate; cAMP: Cyclic adenosine monophosphate; PDE: Phosphodiesterase; SAH: S-adenosyl homocysteine.
Basal adenosine levels in the extracellular fluid of healthy brains (sufficient to tonically activate a substantial fraction of high-affinity adenosine A1 and A2A receptors) is in the range of 25–250 nM. Reuptake of adenosine into the cell, followed by its intracellular metabolism, is responsible for the rapid disappearance of adenosine from the extracellular space.
Adenosine is maintained at this basal level by the following mechanisms:
Facilitated diffusion from the cytosol through nucleoside transporters: this process is dependent on the adenosine concentration gradient on both sides of the membrane. Because of the relatively high activity of intracellular adenosine kinase (converting adenosine to AMP), adenosine concentrations inside cells are normally low, so the net flux through these transporters is inwardly directed. However, under conditions where intracellular adenosine concentrations rise, these transporters can release adenosine. Inhibition of adenosine transport can, therefore, inhibit either adenosine release or adenosine uptake, depending upon the intra- and extra-cellular levels of adenosine;
Active processes driven by the transmembrane sodium gradient: it is presumed that these transporters could be driven in reverse when intracellular adenosine is high and the Na gradient is reduced, such as during hypoxia, ischemia and seizures, and thus could also become mechanisms for adenosine release;
Extracellular conversion of the released adenosine nucleotides (ATP and cAMP) to adenosine through a series of ectoenzymes. Ecto-5'-nucleotidase is the rate limiting enzyme for the formation of adenosine.
The extracellular levels of adenosine are mostly regulated by cytosolic 5'-nucleotidase (converting AMP into adenosine) and adenosine, involved in the conversion of adenosine to AMP (Figure 3). Inhibition of adenosine kinase leads to an increase in extracellular adenosine levels owing to an enhancement of cytoplasmic adenosine concentration. An alternative pathway for the inactivation of extracellular adenosine is its metabolic transformation to inosine by ADA. During any insult to the brain, ADA assumes a prominent role in regulating extracellular adenosine concentrations. Under these conditions, the adenosine transporters are largely inactive, so ADA becomes important in the absence of any other mechanisms for adenosine removal.
Source...