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VOL. 69 (4) ADENOSINE RECEPTORS

This probably reflects the relative importance of neuronal versus non-
neuronal uptake of adenosine since the two enzymatic activities have
apparently different cellular locations with adenosine kinase being
enriched in neurons and adenosine deaminase being more abundant in
astrocytes It should also be mentioned that adenosine can also be
extracellularly deaminated into its inactive metabolite inosine through an
ecto-adenosine deaminase (Franco, Casadó, Ciruela, Saura, Mallol,
Canela and Lluis; 1997), although the relevance of this pathway for
adenosine clearance in the CNS remains to be established (Cunha;
2001b).

An alternative pathway for intracellular metabolization of
adenosine would be via the S-adenosylhomocysteine pathway. But
although this pathway is of relevance for the control of intra- and
extracellular levels of adenosine in cardiomyocytes for instance, it
appears to be of limited importance in the nervous system.

The balance between the effectiveness of releasing and clearing up
adenosine will give raise to a transient extracellular build up of adenosine.
However, the presumably different location of release sites and uptake
sites makes it difficult to estimate an extracellular concentration of
adenosine since one should instead discuss the amplitude of extracellular
adenosine gradient. Pharmacological manipulation of the activity of
adenosine transporters and adenosine receptor responses have lead to an
estimate of the transient concentration of adenosine facing A1 receptors
between 200-400 nM in the rat brain (Dunwiddie and Diao; 1994). This
estimate of an effective concentration of adenosine is similar to those
found in microdialysis studies without stimulating or insulting the CNS
(Hagberg, Andersson, Lacarewicz, Jacobson, Butcher and Sandberg;
1987). Upon stimulation (During and Spencer; 1992) or upon stressful
conditions (Hagberg et al.; 1987) the extracellular amounts of adenosine
can build up to tenths of micromolar.

Adenosine receptors
Despite the fact that adenosine receptors were well characterized
and partially purified the two first adenosine receptors cloned, A1 and
A2A, came from a library of orphan receptors from the dog thyroid
(Maenhaut, Van Sande, Libert, Abramowicz, Parmentier, Vanderhaegen,

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