CO signaling cascade and small molecules used to modulate this pathway. Endogenous carbon monoxide is generated by heme oxygenase (HO). In cells CO reacts with hemeproteins. One of the CO receptors is the guanylyl cyclase (GC) that produces the intracellular messenger cyclic GMP (cGMP). cGMP interacts with the cGMP-dependent protein kinase (PKG), which phosphorylates multiple substrates, and participates in signal propagation. The carbon monoxide donor provides an exogenous source of CO. The natural HO substrate hemin increases CO production because conversion of heme into biliverdin represents the rate-limiting step in heme degradation . The activator of soluble guanylyl cyclase binds to GC, and induces enzyme activation in the absence of CO. The cell permeable analog of cGMP diffuses across the plasma membrane, and thus, activates cGMP-dependent signaling.