Adenosine A 2A receptor promotes collagen type III synthesis via β‐catenin activation in human dermal fibroblasts

Background and Purpose Adenosine A 2A receptor stimulation promotes the synthesis of collagen type I and type III (Col1 and Col3), mediators of fibrosis and scarring. The A 2A receptor modulates collagen balance via cAMP/PKA/p38‐MAPK/Akt pathways. Wnt signalling is important in fibrosis and the cAMP and Wnt pathways converge. Because the A 2A receptor is Gs‐linked and increases cAMP, we determined whether A 2A receptors and Wnt signalling interact. Experimental Approach Total β‐catenin, de‐phosphorylated β‐catenin (canonical activation, de‐phospho β‐catenin) and phosphorylated β‐catenin at Ser 552 (non‐canonical activation, p‐Ser 552 β‐catenin) levels were determined in primary human dermal fibroblasts, cytosol and nucleus, by western blot analysis and fluorescence microscopy, before and after stimulation by A 2A receptor‐selective agonist CGS21680, with/without A 2A receptor‐selective antagonist (SCH56261) pretreatment. β‐Catenin was knocked down by transfection with scrambled‐siRNA or specific‐siRNA, and Col1 and Col3 levels determined by western blots. Key Results CGS21680 stimulation rapidly (15 min) increased cellular β‐catenin levels. Both de‐phospho β‐catenin and p‐Ser 552 β‐catenin levels were also increased. CGS21680 stimulated the translocation of total de‐phospho and p‐Ser 552 β‐catenin to the nucleus. A 2A receptor‐stimulation increased Col1 synthesis similarly in β‐catenin knockeddown and scrambled cells. However, β‐catenin knockdown abolished the increase in Col3 synthesis induced in A 2A receptor‐stimulated fibroblasts. Conclusions and Implications A 2A receptor stimulation promotes Col3 synthesis via the activation of canonical and non‐canonical β‐catenin, consistent with a role for A 2A receptors in dermal fibrosis and scarring.