Autoregulation of cyclic AMP in vascular smooth muscle: a role for adenosine receptors.

The concentration of cyclic AMP within cells is regulated by the activities of adenylyl cyclases and phosphodiesterases (PDE) and the receptors and G proteins that modulate their activities. The extent to which cyclic AMP accumulates in a given cell and activates protein kinase A (PKA) is subject to tight transcriptional and post-transcriptional autoregulation (Table 1). For example, cyclic AMP accumulation in vascular smooth muscle (VSM) is limited through PKA-mediated phosphorylation and activation of PDE3A and PDE4 and through phosphorylation and inhibition of adenylyl cyclases type V/VI (Murthy et al., 2002). Activation of A2A adenosine receptors, which directly couple to Gs to increase cyclic AMP, can also reduce cyclic AMP accumulation in PC12 cells due to up-regulation of PDE4 transcription (Chang et al., 1997) and inhibition of adenylyl cyclase VI (Chern et al., 1995). Adenosine plays a physiologically important role as a dilator of VSM, largely via cyclic AMP-dependent mechanisms. Adenosine dilates VSM by activating Gs coupled A2a and A2b adenosine receptors. Adenosine production is increased in hypoxic tissues and transported across cell membranes to gain access to cell surface receptors on VSM cells (Kiss et al., 2000). In addition, adenine nucleotides released from nerves, platelets, mast cells, macrophages, and endothelial cells are rapidly degraded to adenosine by ectonucleotidases (Zimmermann, 2000). Cyclic AMP represses the ecto-5 -nucleotidase promoter (Spychala et al., 1999) providing a feedback mechanism by which cyclic AMP accumulation may diminish adenosine production from 5 -AMP in the extracellular space. In addition, recent analyses of changes in A3 adenosine receptor transcript and vascular tone in A3 receptor knock-out mice suggest that the Gi-coupled A3 receptors serve as a break on A2Aand A2B-receptor mediated cyclic AMP accumulation and vasodilation (Zhao et al., 2000). Because adenosine receptors modulate cyclic AMP production in VSM, the density of adenosine receptors on the cell surface also serves to regulate cyclic AMP and tone in VSM exposed to adenosine (Table 1). It is notable that the inhibitory A3 receptor undergoes unusually rapid and extensive phosphorylation and internalization (Ferguson et al., 2000) which may result in a rapid loss of A3-receptor mediated inhibitory actions during continuous exposure of VSM to adenosine. Activation of A1 adenosine receptors also indirectly influences cyclic AMP in VSM through the action of an inhibitory prejunctional receptor on sympathetic nerve terminals, resulting in reduced norepinephrine release and reduced VSM -adrenergic receptor activation. In this issue,