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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Purine Release and Metabolism

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Correspondence to Joel M. Linden, Departments of Medicine and Molecular Physiology and Biological Physics, University of Virginia, Box MR4 6012, Health Sciences Center, Charlottesville, Virginia 22902.

Many cells in the nervous system release adenosine and adenine nucleotides

In addition to having a central role in cellular energy metabolism, ATP and diadenosine polyphosphates are classical neurotransmitters that are packaged into secretory granules of neurons and adrenal chromaffin cells. They are released in quanta in response to action potentials, as illustrated in Figure 17-2A. ATP is released from synaptosomal preparations of cortex, hypothalamus and medulla. In cortical synaptosomes, a portion of the ATP that is released is coreleased with acetylcholine (ACh) or norepinephrine (NE), but the majority is released from neurons that are neither adrenergic nor cholinergic. In affinity-purified cholinergic nerve terminals, ATP and ACh are coreleased in a ratio of 1:10. In addition, it has been proposed that there are membrane proteins that can extrude ATP from non-neuronal cells [2].

Figure 17-2. Purine release and metabolism.

Figure 17-2

Purine release and metabolism. A, Prejunctional neuron: Adenine nucleotides are schematically depicted as being stored as cotransmitters in synaptic granules (see enlargement). Amine, aminergic neurotransmitter; ACh, acetylcholine; Ap n A, diadenosine (more...)

Nucleotides can be metabolized in the extracellular space

Ectoenzymes are involved in the rapid metabolism of ATP and other nucleotides [3]. ATP applied to rat brain hippocampal slices is mostly converted to adenosine in less than 1 sec. Some of the enzymes involved in ATP, UTP and nucleoside metabolism are depicted in Figure 17-2B. Inhibitors of these enzymes that are useful as experimental tools are listed in Table 17-1.

Table 17-1. Substrates and Inhibitors of Enzymes Involved in Nucleotide and Nucleoside Metabolism.

Table 17-1

Substrates and Inhibitors of Enzymes Involved in Nucleotide and Nucleoside Metabolism.

EctoATP diphosphohydrolase (ADPase or apyrase) is a plasma membrane-bound enzyme that hydrolyses extracellular ATP and ADP to produce AMP. This enzyme is identical to CD39, an activation marker found on B lymphocytes [4]. A selective inhibitor of ectoATPase that has little effect on P2 receptors is ARL67156 (Table 17-1). This compound potentiates the effect of endogenously released as well as exogenously added ATP. Extracellular AMP is converted to adenosine by ecto-5′-nucleotidase, an enzyme that is attached to the cell surface by a glycosyl phosphatidylinositol linker. 5′-Nucleotidases catalyze the conversion of purine and pyrimidine nucleoside monophosphates to the corresponding nucleosides. CD73 is a 5′-nucleotidase that is found on T and B lymphocytes [5]. Ecto-5′-nucleotidase can be blocked by α, β-methylene-adenosine diphosphate (AOPCP) (Table 17-1). In cytochemical studies, ecto-5′-nucleotidase has been associated with plasma membranes of glial cells and astrocytes, particularly synaptic terminals. Soluble cytosolic 5′-nucleotidases also exist. These are involved in the formation of adenosine during increased metabolic activity. Even a small decrease in ATP can lead to a large increase in the substrate for this enzyme, AMP, because under normal conditions the concentration of ATP is about 50 times higher than that of AMP. The differentiation of neural cells is dependent on 5′-nucleotidase activity, suggesting that adenosine formation from continuously released nucleotides is essential for neuronal survival. 5′-Nucleotidase is phosphorylated and activated by protein kinase C (PKC). In rat brain, ischemia results in an upregulation of 5′nucleotidase on activated astrocytes. This is thought to increase the capacity of damaged tissue to form neuroprotective adenosine. Extracellular adenosine also can be derived from the metabolism of extracellular cAMP by an ectocAMP phosphodiesterase [6]. Stimulation of receptors that increase cAMP accumulation, such as β-adrenergic or vasoactive intestinal peptide (VIP) receptors, in cultured rat cortical neurons causes the accumulation of extracellular adenosine, which can be blocked by inhibition of cAMP transport, cyclic nucleotide phosphodiesterase or 5′-nucleotidase, indicating that extracellular cAMP is a source of the adenosine.

Diadenosine polyphosphates also are degraded in the extracellular space. In neural tissues, the activity of ectodiadenosine polyphosphatases is lower than that of ectoATP-diphospohydrolase. Hence, the diadenosine polyphosphates have a longer half-life in the extracellular space than does ATP.

UDP and UTP are selective agonists of certain P2Y receptors, suggesting that these pyrimidines may play a physiological role in signaling via P2 receptors. It is not yet clear which factors control the release of uridine nucleotides into the extracellular space. UTP can be formed from UDP in the extracellular space by the action of the enzyme nucleoside diphosphokinase, which catalyzes the transfer of the γ-phosphate of nucleoside triphosphates to nucleoside diphosphates, for example, ATP + UDP → ADP + UTP.

Adenosine is considered to be a neuromodulator

Adenosine is not a classical neurotransmitter because it is not stored in neuronal synaptic granules or released in quanta. It gains access to the extracellular space in part from the breakdown of extracellular adenine nucleotides and in part by translocation from the cytoplasm of cells by nucleoside transport proteins, particularly in stressed or ischemic tissues (Fig. 17-2C). Adenosine thus acts as a metabolic messenger that imparts information about the intracellular metabolic state of a particular cell to extracellular-facing receptors on the same cell and on adjacent cells.

Extracellular adenosine is rapidly removed in part by reuptake into cells and in part by degradation to inosine by adenosine deaminases, enzymes that catalyze the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. Adenosine deaminase is mainly cytosolic, but it also occurs as a cell-surface ectoenzyme.

Adenosine and homocysteine are formed from the hydrolysis of S-adenosylhomocysteine (SAH) by the enzyme SAH hydrolase (Fig. 17-2C). Attempts to measure intracellular adenosine are complicated by the fact that over 90% of intracellular adenosine may be weakly bound to this enzyme. SAH is formed from S-adenosylmethionine (SAM), which is a cofactor in transmethylation reactions. SAH is the precursor of a sizable fraction of adenosine under resting conditions, but most adenosine is derived from the 5′-nucleotidase pathway during conditions of hypoxia, ischemia or metabolic stress. Under these conditions, the accumulation of high concentrations of adenosine and the resultant deamination of adenosine also lead to a large increase in inosine. Intracellular adenosine can be reincorporated into the nucleotide pool upon phosphorylation by the cytosolic enzyme adenosine kinase. In normoxic resting tissues, most adenosine is rephosphorylated since the K m of adenosine kinase is 10 to 100 times lower than the K m of adenosine deaminase. Deamination, leading to a large accumulation of inosine, becomes the major pathway of adenosine metabolism when adenosine concentrations are elevated because maximal adenosine kinase activity is much less than maximal adenosine deaminase activity. By elevating adenosine, inhibitors of adenosine kinase or adenosine deaminase produce adenosine-like actions in laboratory animals. Concentrations of adenosine and inosine in the interstitial fluid of brain and other tissues are increased when oxygen supply exceeds oxygen demand. The effect of adenosine is to increase oxygen delivery by dilating most vascular beds and generally to decrease oxygen demand by reducing cellular energy utilization. In the brain, this is usually manifested as a decrease in neuronal firing and in the diminished release of excitatory neurotransmitters.

Adenosine and inosine can be transported across cell membranes in either direction by a membrane-associated, facilitated nucleoside transport protein. Concentrative transporters also have been identified [7]. Messenger RNA for a pyrimidine-selective Na+-nucleoside cotransporter (rCNT1) and a purine-selective Na+-nucleoside cotransporter (rCNT2) are found throughout the rat brain. Most degradation of adenosine is intracellular, as evidenced by the fact that inhibitors of adenosine transport, such as dipyridamole, increase interstitial concentrations of adenosine. Dipyridamole is clinically used to elevate adenosine in coronary arteries and to produce coronary vasodilation. In high doses, dipyridamole can accentuate adenosine receptor-mediated actions in the CNS, resulting in sedation and sleep, anticonvulsant effects, decreased locomotor activity and decreased neuronal activity.

Hypoxanthine is derived from inosine by the enzyme nucleoside phosphorylase. Hypoxanthine can be converted to inosine monophosphate (IMP) by hypoxanthine-guanine phosphoribosyl transferase (HGPRT), one of the enzymes of the purine salvage pathway. Lesch-Nyhan syndrome is a severe neurological disorder caused by a deficiency of HGPRT (see Box 17-1). AMP can be formed from IMP by insertion of an amino group at C-6 in place of the carbonyl oxygen. This is a two-step reaction involving the formation of adenylosuccinate as an intermediate. Unsalvaged hypoxanthine is oxidized to xanthine, which is further oxidized to uric acid by xanthine oxidase (Fig. 17-3). Molecular oxygen, the oxidant in both reactions, is reduced to H2O2 and other reactive oxygen species. In humans, uric acid is the final product of purine degradation and is excreted in the urine.

Box Icon

Box 17-1

Inherited Diseases of Purine Metabolism. Lesch-Nyhan syndrome (LNS) is an X-linked recessive inherited disorder usually evident at six to ten months of age with choreiform movements, compulsive self-mutilation, spasticity, mental retardation, hyperuricemia and (more...)

Figure 17-3. Adenosine metabolites.

Figure 17-3

Adenosine metabolites. Adenosine is converted to inosine by adenosine deaminase. Removal of the ribose by nucleoside phosphorylase produces hypoxanthine, which is sequentially oxidized to xanthine and uric acid by xanthine oxidase.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28118

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