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B. B. FREDHOLM ANAL. REAL ACAD. NAL. FARM.

1996, Arslan and Fredholm; 2000), probably via PKA-dependent
phosphorylation of Raf-1. The adenosine A2B receptor is the only subtype
that has so far been shown to activate not only ERK1/2, but also JNK and
p38 perhaps via activation of Gq/11, PLC, genistein-insensitive tyrosine
kinases, ras, B-raf and MEK1/2 (Gao, Chen, Weber and Linden; 1999).
Studies in transfected cells show a nearly 100-fold higher potency of both
NECA and adenosine in inducing ERK1/2 phosphorylation than in
inducing cAMP production. The EC50 value for ERK1/2 phosphorylation
in transfected CHO lies in the nanomolar range, whereas cAMP
production is half-maximally activated around 1-5 µM NECA. This
emphasizes that G protein-coupled adenosine receptors can have
substantially different potencies on different signaling pathways in the
same cellular system. The adenosine A3 receptor activates ERK1/2 in
human fetal astrocytes and in transfected CHO cells (Schulte and
Fredholm; 2000).

Adenosine A2A receptors in striatum interact with
dopaminergic mechyanisms
In 1974 Kjell Fuxe and Urban Ungerstedt showed that theophylline could
by itself induce the same type of rotation-behavior that was induced by
drugs that directly or indirectly stimulated dopamine receptors and that it
could markedly enhance dopamine-mediated effects (Fuxe and
Ungerstedt; 1974). In that study the effect was interpreted as secondary to
blockade of phosphodiesterase (PDE) and was therefore taken as evidence
for an important role of cyclic AMP as a mediator of dopamine actions.
However, in a follow-up study where I (BF) was involved several
different PDE inhibitors were examined and it was found that the potency
of the drugs fitted much better with their potency as adenosine antagonists
(or enhancers) than their potency as PDE inhibitors (Fredholm, Fuxe and
Agnati; 1976). Together these studies showed that methylxanthines,
probably by blocking adenosine receptors, could potentially be used as
treatment in PD.

Studies, in two laboratories, of dopamine stimulated adenylyl cyclase in
brain also showed that methylxanthines could lower “basal” enzyme
activity and that adenosine could stimulate it (Fredholm; 1977, Premont,
Perez and Bockaert; 1977). This was observed in dopamine-rich areas of

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