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Abstract. Extracellular nucleotides and nucleosides act as signaling molecules involved in a wide spectrum of biological effects. Their levels are controlled by a complex cell surface-located group of enzymes called ectonucleotidases. There are four major families of ectonucleotidases, nucleoside triphosphate diphosphohydrolases (NTPDases/CD39), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases and ecto-5'-nucleotidase. In the last few years, substantial progress has been made toward the molecular identification of members of the ectonucleotidase families and their enzyme structures and functions. In this review, there is an emphasis on the involvement of NTPDase and 5'-nucleotidase activities in disease processes in several tissues and cell types. Brief background information is given about the general characteristics of these enzymes, followed by a discussion of their roles in thromboregulatory events in diabetes, hypertension, hypercholesterolemia and cancer, as well as in pathological conditions where platelets are less responsive, such as in chronic renal failure. In addition, immunomodulation and cell-cell interactions involving these enzymes are considered, as well as ATP and ADP hydrolysis under different clinical conditions related with alterations in the immune system, such as acute lymphoblastic leukemia (ALL), Bchronic lymphocytic leukemia (B-CLL) and infections associated with human immunodeficiency virus (HIV). Finally, changes in ATP, ADP and AMP hydrolysis induced by inborn errors of metabolism, seizures and epilepsy are discussed in order to highlight the importance of these enzymes in the control of neuronal activity in pathological conditions. Despite advances made toward understanding the molecular structure of ectonucleotidases, much more investigation will be necessary to entirely grasp their role in physiological and pathological conditions.
Abstract. Extracellular nucleotides and nucleosides act as signaling molecules involved in a wide spectrum of biological effects. Their levels are controlled by a complex cell surface-located group of enzymes called ectonucleotidases. There are four major families of ectonucleotidases, nucleoside triphosphate diphosphohydrolases (NTPDases/CD39), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases and ecto-5'-nucleotidase. In the last few years, substantial progress has been made toward the molecular identification of members of the ectonucleotidase families and their enzyme structures and functions. In this review, there is an emphasis on the involvement of NTPDase and 5'-nucleotidase activities in disease processes in several tissues and cell types. Brief background information is given about the general characteristics of these enzymes, followed by a discussion of their roles in thromboregulatory events in diabetes, hypertension, hypercholesterolemia and cancer, as well as in pathological conditions where platelets are less responsive, such as in chronic renal failure. In addition, immunomodulation and cell-cell interactions involving these enzymes are considered, as well as ATP and ADP hydrolysis under different clinical conditions related with alterations in the immune system, such as acute lymphoblastic leukemia (ALL), Bchronic lymphocytic leukemia (B-CLL) and infections associated with human immunodeficiency virus (HIV). Finally, changes in ATP, ADP and AMP hydrolysis induced by inborn errors of metabolism, seizures and epilepsy are discussed in order to highlight the importance of these enzymes in the control of neuronal activity in pathological conditions. Despite advances made toward understanding the molecular structure of ectonucleotidases, much more investigation will be necessary to entirely grasp their role in physiological and pathological conditions.
Several studies have suggested a role of extracellular ATP in synaptic plasticity. The signaling actions induced by extracellular ATP are directly correlated to the activity of a group of ectonucleotidases, which includes an ecto-ATPase (EC 3.6.1.3), an ATP diphosphohydrolase (apyrase, EC 3.6.1.5), and a 5′-nucleotidase (EC 3.1.3.5). These ectoenzymes trigger enzymatic conversion of ATP to adenosine, an important neuromodulator. Our studies have shown that ectonucleotidase activities are modulated in physiological and pathological situations able to induce synaptic plasticity, such as memory, epilepsy, and ischemia. Synaptosomal ectonucleotidase activities from hippocampus and entorhinal cortex were inhibited after the training session in a step-down inhibitory avoidance task in rats. Considering that adenosine has anticonvulsant effects, ectonucleotidase activities were determined after the induction of epilepsy by several animal models, such as pilocarpine, kainic acid, and kindling models. ATP diphosphohydrolase and 5′-nucleotidase activities from synaptosomes of hippocampus and cerebral cortex of rats significantly and differently increased after induction of status epilepticus by pilocarpine, kainic acid, or kindling models. Furthermore, significant changes have been observed in ATP diphosphohydrolase and 5′-nucleotidase after ischemia and reperfusion in hippocampal synaptosomes of rats. The demonstration that ectonucleotidases presented the activities altered after a memory task, or the induction of animal models of epilepsy or ischemia-reperfusion, suggests that these enzymes can act in the regulation of synaptic activity, controlling ATP and adenosine levels, depending on the synaptic plasticity developed, in physiological or pathological conditions. Drug Dev. Res. 52:57-65, 2001.
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