Purine Signaling and Potential New Therapeutic Approach: Possible Outcomes of NTPDase Inhibition

Abstract

Interest for extracellular nucleotides has increased since the pioneer work of Burnstock in the early seventies. Research on cellular functions modulated by purines and pyrimidines has led to the identification and characterization of the different components of purine signaling, namely purinoceptors and ecto-nucleotidases. Receptors for tri- and diphosphonucleosides, known as P2 nucleotide receptors, are designated either P2Y receptors, for those coupled to G-proteins, or P2X for those which are ligand gated-ion channels. Ecto-nucleoside triphosphate diphosphohydrolase (NTPDase; EC 3.6.1.5), previously identified as ecto-ATPase, ecto-ATPDase or CD39, is now considered as the main ecto-nucleotidase responsible for the sequential hydrolysis of beta and gamma phosphates of tri- and diphosphonucleosides. More recently, research has been focused on the development of specific agonists and antagonists to P2 purinoceptors. The need to develop specific inhibitors for NTPDase to understand the role of this enzyme has clearly emerged. This paper covers the development of specific molecules targeting purinergic signaling, more specifically the inhibition of NTPDase and their impact on the different physiological systems.

Ectonucleotidases in the kidney

“…Recent reports demonstrated that ARL 67156 is a weak competitive inhibitor of NTPDase1, NTPDase3 and NPP1, with K i for the human enzymes of 11± 3, 18± 4 and 12± 3 µM, respectively [17,68]. Another ATP analogue, 8-thiobutyladenosine 5′-triphosphate (8-BuS-ATP), and 1-naphthol-3,6-disulfonic acid (BG0136), appear of interest, but so far they have only been characterised on a NTPDaseactive fraction from bovine spleen membranes [69,70]. In addition, recent evidence indicates that some polyoxometalate anionic complexes inhibit rat NTPDases [71], that a uridine-5′-carboxamide derivative selectively inhibits human NTPDase2 [72] and that a novel monoclonal antibody selectively inhibits human NTPDase3 [73].…”

Cross-immunoreactivity between anti-potato apyrase antibodies and mammalian ATP diphosphohydrolases: potential use of the vegetal protein in experimental schistosomiasis

“…NTPDases have been described in hepatocytes, epithelial cells of the bile duct system, vascular cells, platelets, lymphocytes, monocytes, and macrophages cells (Gendron et al 2002, Bigonnesse et al 2004, Ivanenkov et al 2005. Eight members of the mammalian NTPDases family have been identified, including six membrane-bound enzymes (NTPDases 1-4, 7, and 8) and two secreted enzymes (NTPDases 5 and 6) (Gendron et al 2002, Bigonnesse et al 2004, Ivanenkov et al 2005.…”

“…Eight members of the mammalian NTPDases family have been identified, including six membrane-bound enzymes (NTPDases 1-4, 7, and 8) and two secreted enzymes (NTPDases 5 and 6) (Gendron et al 2002, Bigonnesse et al 2004, Ivanenkov et al 2005. The phylogenetic tree obtained for the NTPDases family (see Fig.…”

“…Potato apyrase was one of the first proteins of this family to be purified (Traverso-Cori et al 1965). Since then, a number of ATP diphosphohydrolases differing in their catalytic properties and subcellular localization have been identified from different species, such as parasites, mammals and plants, and play important roles in the control of nucleotides levels in a variety of physiological processes (Coimbra et al 2002, Gendron et al 2002, Ivanenkov et al 2005.Studies in our laboratory showed that potato apyrase purified from Solanum tuberosum presents remarkable im- (Vasconcelos et al 1996, Faria-Pinto et al 2004) and cellular immune responses in mice, inducing a mixed Th1/Th2-type cytokine secretion profile (unpublished data). Rabbit policlonal antibodies against purified potato apyrase showed strong cross-immunoreactivity with partially purified S. mansoni ATP diphosphydrolase isoforms, suggesting that the parasite and vegetable proteins share conserved epitopes (Vasconcelos et al 1996, Faria-Pinto et al 2004).…”

“…Potato apyrase was one of the first proteins of this family to be purified (Traverso-Cori et al 1965). Since then, a number of ATP diphosphohydrolases differing in their catalytic properties and subcellular localization have been identified from different species, such as parasites, mammals and plants, and play important roles in the control of nucleotides levels in a variety of physiological processes (Coimbra et al 2002, Gendron et al 2002, Ivanenkov et al 2005.…”