Ectonucleotidase

Ectonucleotidases consist of families of nucleotide metabolizing enzymes that are expressed on the plasma membrane and have externally orientated active sites. These ectoenzymes operate in concert or consecutively and metabolize nucleotides to the respective nucleoside analogs. They have the potential to decrease extracellular concentrations of nucleotides and to generate nucleosides. The relative contribution of the distinct enzymes to the modulation of purinergic signaling may depend on the availability and preference of substrates and on cell and tissue distribution.

Ectonucleotidases modulate P2-receptor-mediated signaling. Alterations in extracellular nucleotide levels can increase or decrease P2 activity or lead to P2 receptor desensitization. Desensitization of P2 receptors is dose dependent. In vitro the desensitization of anion secretion responses requires 10-min preincubations with the P2Y2 receptor agonist UTP. Recovery from UTP or ATP-induced desensitization can either be rapid (<10 min) at preincubation concentrations of approximately 2 µM or requires progressively longer time periods at higher concentrations. Furthermore, generation of extracellular adenosine not only abrogates nucleotide-mediated effects but also activates adenosine receptors, often with opposing (patho-) physiological effects.

Ectonucleotidases also produce the key molecules for purine salvage and consequent replenishment of ATP stores within multiple cell types. Indeed, although nucleotides do not appear to be taken up by cells, dephosphorylated nucleoside derivatives interact with several specific transporters to enable intracellular uptake via membrane passage.

There are four major families of ectonucleotidases in the liver microenvironment namely CD39/NTPDases (ecto-nucleotide triphosphate diphosphohydrolases), Nucleotide pyrophosphatase/phosphodiesterase (NPP)-type ecto-phosphodiesterases, alkaline phosphatases and ecto-5’-nucleotidases/CD73