Adenosine A₃ receptor (A₃R)

Adenosine A₃ receptor (A₃R) is an ADORA3-encoded G protein-coupled receptor involved in GPCR signaling^[1]. Mechanistically, A₃R activation can inactivate adenylyl cyclase and stimulate phospholipase C or D, linking the receptor to cyclic nucleotide and phospholipid signaling^[2]. In inflammatory disease models, A₃R is overexpressed in inflammatory cells, and the agonist CF502 inhibited fibroblast-like synoviocyte proliferation through deregulation of the PI3K-PKB/Akt-NF-κB pathway in rheumatoid arthritis samples and adjuvant-induced arthritis rats^[3]. In ischemia-reperfusion models, selective A₃R agonists CP-532,903 and CP-608,039 reduced myocardial infarct size, supporting A₃R activation as an experimental cardioprotection strategy^[4]. Compared with related adenosine receptor isoforms, A₃R selectivity remains a central design requirement because orthosteric binding sites are similar across adenosine receptors^[5]. Structural studies further distinguished A₃R by defining agonist-bound A₃R-G protein complexes with adenosine, NECA, m⁶A, i⁶A, and namodenoson^[6]. For research applications, selective antagonists such as VUF5574 and K18 provide tools for functional assays, receptor characterization, ligand discovery, and disease-oriented pharmacology^[5][7].