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VOL. 73 (2), 537-566, 2007 ECTO-NUCLEOTIDASES, MOLECULAR PROPERTIES...

ECTO-NUCLEOTIDASES AND PURINERGIC SIGNALING

It is obvious that the broad spectrum of ecto-nucleotidase enzyme
species as well as the considerable variability of their catalytic
properties allows for multiple modulations of purinergic signaling-
depending on type and combination of enzymes as well as receptors.
Ecto-nucleotidases could for example (1) inactivate P2 receptors
sensitive to nucleoside triphosphates by directly hydrolyzing a
nucleoside triphosphate to the inactive nucleoside monophosphate,
(2) inactivate P2 receptors sensitive to nucleoside triphosphates and
at the same time (by generating the nucleoside diphosphate)
transiently or tonically produce agonists for nucleoside diphosphate
receptors, (3) inactivate receptors for e.g. diadenosine polyphosphates
and at the same time generate the physiologically active ligands Ap4,
ATP or ADP, (4) prevent P2 receptor desensitization, (5) generate the
P1 receptor agonist adenosine from extracellular ATP. Following
release of ATP, this allows for complex signaling mechanisms in
cellular networks that can involve both, P2 and P1 receptor activation.
Therefore a detailed analysis of nucleotide signaling pathways
requires information on the identity and exact location of both ecto-
nucleotidase and purinergic receptor subtypes for each individual
cellular setting investigated.

In vitro studies using recombinant proteins, mimicking different
combinations of receptors and enzymes underline this notion. (83).
The data demonstrate that ecto-nucleotidases can selectively modulate
the effective agonist concentration at P2Y1 receptors on identical
or neighboring cells, either by degrading ATP or by generating
ADP from ATP. In addition, colocalized ecto-nucleotidases, by
reducing levels of constitutively released nucleotide, reduce receptor
desensitization. Preventing receptor desensitization following tonic or
acute nucleotide release may be an important function of ecto-
nucleotidases.

This close interaction between enzymes and ecto-nucleotidases
is also of immediate relevance in situ. The interaction between
the two ecto-nucleotidases NTPDases1 and NTPDase2 is of pivotal
importance for the control of vascular platelet activation. NTPDase1
is expressed by endothelial cells, vascular smooth muscle cells and
to a small extent by red blood cells and platelets. Due to its capacity

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