The adenosine A1 and A2 receptors were initially subdivided on the basis of their inhibiting and stimulating adenylyl cyclase, respectively. Indeed, A1 and A2 receptors are coupled to members of the Gi group and Gs group of G proteins, respectively. 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 Gof in striatum (Kull et al. 2000). Endogenous A2b receptors of HEK 293 cells, human HMC-1 mast cells and canine BR mast cells are dually coupled to Gs and Gq (Auchampach et al. 1997; Linden et al. 1999).
After activation of the G proteins, enzyme and ion channel activity is modulated. A1 receptors mediate inhibition of adenylyl cyclase, activation of several types of K+-channels (probably via |3,y-subunits), inactivation of N, P, and Q-type Ca2+ channels, activation of phospholipase CP etc. The same appears to be true for A3 receptors. In CHO cells transfected with the human A3 adenosine receptor both adenylyl cyclase inhibition and a Ca2+ signal are mediated via a Gi/o-dependent pathway (Klotz et al. 2000). Given that many of the steps in the signalling 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 (Baker et al. 2000). Both A2a and A2b receptors stimulate the formation of cyclic AMP, but other actions, including mobilization of intracellular calcium have also been described (Mirabet et al. 1997). Actions of adenosine A2a receptors on neutrophil leukocytes are due in part to cyclic AMP (Fredholm et al. 1996; Sullivan et al. 2001) but cyclic AMP-independent effects of A2a receptor activation in these cells have also been suggested (Cronstein 1994).
Activation of A1 receptors can dose- and time-dependently activate ERK1/2 via P,y-subunits released from pertussis toxin-sensitive G;/o proteins and phosphoinositol-3-kinase (Faure etal. 1994; Dickenson et al. 1998; Schulte and Fredholm 2000). Activation of A2a receptors also increases MAPK activity (Sexl etal. 1997) but the signalling pathways used by the A2A receptor seem to vary with the cellular background and the signalling machinery that the cell possesses (Seidel et al. 1999). A2a receptor activation may not only stimulate, but also inhibit ERK phosphorylation (Hirano etal. 1996; Arslan and Fredholm 2000), probably via PKA-dependent phosphorylation of Raf-1. The adenosine A2b receptor is the only subtype which so far has been shown to activate not only ERK1/2, but also JNK and p38 (Feoktistov et al. 1999), perhaps via activation of Gq/11, PLC, genistein-insensitive tyrosine kinases, ras, B-raf and MEK1/2 (Gao et al. 1999). Studies in transfected cells (Schulte and Fredholm 2000) show a nearly 100-fold higher potency of both NECA and adenosine in inducing ERK1/2 phosphorylation than in inducing cyclic AMP production. The EC50 value for ERK1/2 phosphorylation in transfected CHO cells lies in the nanomolar range, whereas cyclic AMP production is half-maximally activated around 1-5 ^M NECA. This emphasizes that G protein-coupled adenosine receptors can have substantially different potencies on different signalling pathways in the same cellular system. The adenosine A3 receptor activates ERK1/2 in human foetal astrocytes (Neary et al. 1998) and in CHO cells (Schulte and Fredholm 2000).
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