FIGURE 10.

Schematic representation of PKA–, EPAC1–, and AKAP2–PKA-mediated signaling pathways induced by adenosine and ATPγS in HLMVECs. We hypothesize that adenosine stimulates increased cAMP levels in HLMVECs through A2B receptors which leads to the activation of two downstream targets, PKA and EPAC1. In contrast, ATPγS dependent signaling is mediated by P2Y4 and P2Y12 receptors leading to the cAMP-independent activation of PKA that requires AKAP2 expression. The effect of both, adenosine and ATPγS converge at the level of MLCP via increased phosphorylation of the regulatory subunit MYPT1 resulting in MLCP deinhibition, which leads to MLC20 dephosphorylation and finally to EC barrier strengthening. ATPγS: adenosine 5′-[γ-thio]-triphosphate; cAMP: cyclic adenosine monophosphate; EC: endothelial cell; EPAC1: exchange factor 3; HLMVEC: human lung mic rovascular endothelial cell; MLC20: myosin light chain 2; MLCP: myosin light chain phosphatase; PKA: protein kinase A