Is cAMP Good or Bad?

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See related article, pages 675–681 Endothelium of the vascular system forms a semipermeable barrier between blood and the interstitial space that serves to control and restrict the luminal to abluminal movement of water, plasma proteins, and other solutes.1 During inflammation, mediators such as thrombin, histamine, and platelet activating factor (PAF) induce vascular leakage defined as an increased endothelial permeability to plasma proteins. In the lung, disruption of the barrier formed by pulmonary microvascular endothelial cells (PMVECs) occurs during inflammatory disease states such as acute lung injury and acute respiratory distress syndrome. Endothelial permeability to macromolecules occurs via the formation of small gaps between (paracellular) or through (transcellular) cells and is controlled by cell shape and cell adhesion through a balance of opposite mechanical forces; contractile forces generated by actomyosin motor function, tethering forces generated by adhesive proteins at the cell–cell border, and focal adhesions at the cell–matrix border.2 Because of its central role in mechanical processes, Ca2+ is an important regulator of endothelial permeability. Intracellular Ca2+ concentration ([Ca2+]i) is increased in PMVECs on binding of proinflammatory mediators to their respective membrane receptors, and subsequent activation of the Gq protein–mediated signaling cascade. In particular, this rise in [Ca2+]i is essential for the generation of endothelial cell paracellular gaps. Other downstream major actors in this Ca2+-sensitizing cascade include PKC, Ca2+-dependent myosin light chain kinase (MLCK), and the monomeric GTPase RhoA. Whereas elevated [Ca2+]i increases endothelial barrier permeability, increased cAMP has the opposite effect.3 Changes in this ubiquitous second messenger are governed by modulating the cAMP synthesis and cAMP hydrolysis machinery. In endothelial cells, most of cAMP synthesis is accounted for by the Ca2+-inhibited type 6 adenylyl cyclase (AC6),4 and …