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VOL. 69 (4) ADENOSINE RECEPTORS

point out that the extremely important contributions by other scientists
will not be covered here.

Regulation of the levels of adenosine
It should be clearly understood that adenosine does not act as a
classical hormone or neurotransmitter: it is not stored in vesicles, it is not
released by exocytosis, it does not appear to transfer information from the
pre- to the postsynaptic components and it does not act only or
predominantly in synapses. Instead, adenosine fulfils a double role (see
Cunha; 2001a), acting both as a homeostatic trans-cellular messenger, and
as a modulator, controlling i.a. neurotransmitter release and neuronal
excitability.

Adenosine can appear in the extracellular milieu through three
different mechanisms: 1) the release of adenosine as such through
nucleoside transporters upon increase of the intracellular levels of
adenosine; 2) the extracellular formation of adenosine through the ecto-
nucleotidase pathway on release of adenine nucleotides, and 3) the
extracellular formation of adenosine on release of cAMP (reviewed in
Dunwiddie and Masino; 2001). The third pathway has been found to be of
minor importance in more integrated preparations when physiological
parameters affected by adenosine are being studied (Brundege, Diao,
Proctor and Dunwiddie; 1997).

The idea that adenosine is mostly released as such through the
different classes of nucleoside transporters is probably the most popular
hypothesis. It was formulated essentially by analogy with the way
extracellular adenosine is generated upon cytotoxic insults, like hypoxia
or metabolic poisoning (for references, see Cunha; 2001a, Dunwiddie and
Masino; 2001, Latini and Pedata; 2001). In stressful situations, there is an
imbalance between energy supply and demand, leading to a net hydrolysis
of ATP. Via a series of steps, this ATP is converted to adenosine, leading
to a dramatic increase in the intracellular concentration of adenosine,
which, at rest, is around 50 nM. The presence of non-concentrative bi-
directional adenosine transporters will then force extracellular adenosine
to rise in parallel with intracellular adenosine. Given that intracellular

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