Differential role of the carboxy-terminus of the A(2B) adenosine receptor in stimulation of adenylate cyclase, phospholipase Cbeta, and interleukin-8.

In human mast cells and microvascular endothelial cells, the A(2B) adenosine receptor controls at least three independent signaling pathways, i.e., Gs-mediated stimulation of adenylate cyclase, Gq-mediated stimulation of phospholipase Cbeta, and Gs/Gq-independent upregulation of IL-8. Functional analysis of cells transfected with full-length and truncated receptor constructs revealed that the A(2B) receptor C-terminus is important for coupling to Gs and Gq proteins. Removal of the entire cytoplasmic portion in the A(2B) receptor C-terminus rendered it incapable of stimulating adenylate cyclase and phospholipase Cbeta. Conversely, removal of the distal 16 amino acids facilitated signal transduction from the receptor to the downstream Gs but not Gq proteins. However, the A(2B) receptor C-terminus is not essential for upregulation of IL-8. Analysis of chimeric A(2A)/A(2B) receptors demonstrated that only chimeras containing the third intracellular loop of the A(2B) receptor mediated agonist-dependent IL-8 reporter stimulation, suggesting that this domain is important for upregulation of IL-8.