Page 96 - 73_02

HERBERT ZIMMERMANN Y COLS. AN. R. ACAD. NAC. FARM.

Synaptic transmission: Some of the best evidence for a modulatory
role for ecto-nucleotidases in purinergic signal transmission stems
from investigations of the peripheral nervous system. Stable analogues
of ATP are up to a hundred times more potent than ATP in causing
smooth muscle contraction. ARL 67156 potentiates contractions
caused by nerve stimulation or application of ATP (116). This suggests
that ecto-nucleotidases tonically attenuate ATP-mediated signal
transmission, an effect relieved by the enzyme inhibitor. At
hippocampal synapses, ATP is rapidly hydrolyzed to adenosine that
in turn activates pre- or postsynaptic receptors, thereby modulating
synaptic transmission (79, 117, 118). In accordance with these
observations, the inhibitory synaptic effects of nucleotides or of
adenosine are abrogated in mice lacking A1 adenosine receptors (119).

Astrocyte signaling: ATP is a major extracellular mediator in the
propagation of Ca2+-waves between astrocytes in various brain
regions and within the retina. Ca2+-waves may be involved in the
modulation of synaptic transmission and in neuron-glia bi-
directional communication (120, 121). While inhibition of ecto-
nucleotidase activity facilitates and addition of potato apyrase
attenuates the physiological action of ATP in these experimental
settings, sites and extent of endogenous hydrolysis and the type of
endogenous ecto-nucleotidase involved need to be identified.

Microglia: Of all neuronal and glial cells, microglia stands out for
its high surface-located nucleotidase activity that has been identified
as NTPDase1 (61, 62). Ischemia enhances long-term microglial ecto-
nucleotidase expression. ATP stimulates microglia to release various
biologically active substances, induces chemotaxis of cultured
microglia and can, at high doses, induce microglial death (122). In
addition, spinal cord microglia is involved in inducing tactile allodynia
caused by peripheral nerve injury which is gated by P2X4 receptors
(123). The functional role of the very high microglial ecto-nucleotidase
activity needs to be elucidated. It may increase the threshold for ATP-
mediated microglial activation and the subsequent release of signaling
substances or may prevent receptor desensitization.

Cerebral vascular control: NTPDase1 knockout mice reveal
increased cerebral infarct volumes and reduced postischemic
perfusion following middle cerebral artery occlusion. Similarly, a

554