SENSITIZING SOLUBLE GUANYLYL CYCLASE TO BECOME A HIGHLY CO-SENSITIVE ENZYME

It took at least a decade to realize that the toxic gas NO is the phys iological activator of soluble guanylyl cyclase (sGC), thereby acting as a signaling molecule in the nervous and cardiovascular systems. Des pite its rather poor sGC-activating property, CO has also been implica ted as a physiological stimulator of sGC in neurotransmission and vaso relaxation. Here, we establish YC-1 as a novel NO-independent sGC acti vator that potentiates both CO- and NO-induced sGC stimulation. As thi s potentiating effect is also observed with protoporphyrin IX which ac tivates sGC independently of a gaseous ligand, we conclude that stabil ization of the enzyme's active configuration is the underlying mechani sm of YC-1's action. Moreover, the results obtained with YC-1 reveal t hat CO is capable of stimulating sGC to a degree similar to NO, and th us provide the molecular basis for CO functioning as a signaling molec ule.