Ectonucleoside triphosphate diphosphohydrolases and ecto-5'-nucleotidase in purinergic signaling: how the field developed and where we are now

Abstract

Geoffrey Burnstock will be remembered as the scientist who set up an entirely new field of intercellular communication, signaling via nucleotides. The signaling cascades involved in purinergic signaling include intracellular storage of nucleotides, nucleotide release, extracellular hydrolysis, and the effect of the released compounds or their hydrolysis products on target tissues via specific receptor systems. In this context ectonucleotidases play several roles. They inactivate released and physiologically active nucleotides, produce physiologically active hydrolysis products, and facilitate nucleoside recycling. This review briefly highlights the development of our knowledge of two types of enzymes involved in extracellular nucleotide hydrolysis and thus purinergic signaling, the ectonucleoside triphosphate diphosphohydrolases, and ecto-5'-nucleotidase.

Keywords: ATP; Adenosine; E-NTPDase; Ecto-5′-nucleotidase; Geoffrey Burnstock; History.

Fig. 1

Schematic representation of synthesis, storage, release, and inactivation of ATP at purinergic nerves as depicted by Burnstock for purinergic neuromuscular junctions in 1972 [3]. Reproduced with permission from the American Society for Pharmacology and Experimental Therapeutics

Fig. 2

Membrane topology of NTPDases 1, 2, 3, and 8 and eN (ecto-5′-nucleotidase). The boxes in the NTPDase extracellular loop represent the position of the apyrase conserved regions. eN is GPI-anchored. The GPI anchor may be cleaved by endogenous phospholipases resulting in the release of the enzyme into the interstitial space. NTPDases have the potential to form homo-oligomeric complexes (dimers to tetramers). eN exists and functions as a noncovalent dimer [1]. The hydrolysis cascade is shown for ATP to adenosine. But it applies also to other nucleoside triphosphates (NTP → NDP → NMP; NMP → nucleoside). Purinergic receptors activated by nucleotides and adenosine are indicated below

Fig. 3

Ectodomain structure of NTPDase1 and eN. To mark the active site of rat NTPDase1 (chain A of protein data bank [pdb] id 3zx3), the non-hydrolysable ATP analogue AMPPNP (β,γ-imidoadenosine 5′-triphosphate) (red) and a calcium ion (black sphere) have been superimposed from rat NTPDase2 structure (pdb id 3cja). For the homodimeric eN, the domains of one monomer are depicted in blue and green, whereas the other subunit is shown in yellow and orange. The catalytic zinc ions are shown in black and the structural Ca²⁺ ions in gray. Adenosine (red) is bound to the C-terminal domains of the open state structure of eN (pdb id 4h2i), and AMPCP (adenosine 5′-[α,β-methylene]diphosphate) (red) is bound to the active site in the closed state structure (pdb id 4h2i). The figure was kindly provided by Norbert Sträter, Leipzig, Germany