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VOL. 69 (4) ADENOSINE RECEPTORS

The A3 receptor is also Gi coupled. In addition, there is some
evidence from transfection experiments that the adenosine receptors may
signal via other G proteins, but it is not known if such coupling is
physiologically important. Recently, evidence was presented that whereas
the A2A receptor is coupled to Gs in most peripheral tissues it is coupled to
Golf in striatum (Kull, Svenningsson and Fredholm; 2000). Endogenous
A2B receptors of HEK 293 cells, human HMC-1 mast cells and canine BR
mast cells may be dually coupled to Gs and Gq

After activation of the G proteins, enzymes and ion channels are
affected as can be predicted from what is known about G protein
signaling. Thus, A1 receptors mediate inhibition of adenylyl cyclase,
activation of several types of K+-channels (probably via ?,?-subunits),
inactivation of N, P and Q-type Ca2+ channels, activation of
phospholipase C? etc. The same appears to be true for A3 receptors. In
CHO cells transfected with the human adenosine A3 receptor both
adenylyl cyclase inhibition and a Ca2+ signal are mediated via a Gi/o-
dependent pathway. Given that many of the steps in the signaling cascade
involve signal amplification it is not surprising that the position of the
dose-response curve for agonists will depend on which particular effect is
measured Both A2A and A2B receptors stimulate the formation of cAMP,
but other actions, including mobilization of intracellular calcium (e.g.
Mirabet, Mallol, Lluis and Franco; 1997), have also been described.
Actions of adenosine A2A receptors on neutrophil leukocytes are due in
part to cAMP, but cyclic AMP-independent effects of A2A receptor
activation in these cells have also been suggested.

Activation of A1 receptors can dose and time dependently activate
ERK1/2 via ?,?-subunits released from pertussis toxin-sensitive Gi/o
proteins and phosphoinositol-3-kinase.

Activation of A2A receptors also increases MAPK activity (Sexl,
Mancusi, Holler, Gloria-Maercker, Schutz and Freissmuth; 1997) but the
signaling pathways used by the A2A receptor seem to vary with the
cellular background and the signaling machinery that the cell possesses
(Seidel, Klinger, Freissmuth and Holler; 1999). A2A receptor activation
may not only stimulate, but also inhibit ERK phosphorylation (Hirano,
Aoki, Ogasawara, Kodama, Waga, Sakanaka, Shimizu and Nakamura;

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