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 physiological activator of soluble guanylyl cyclase (sGC), thereby acting as a signaling molecule in the nervous and cardiovascular systems. Despite its rather poor sGC-activating property, CO has also been implicated as a physiological stimulator of sGC in neurotransmission and vasorelaxation. Here, we establish YC-1 as a novel NO-independent sGC activator that potentiates both CO- and NO-induced sGC stimulation. As this potentiating effect is also observed with protoporphyrin IX which activates sGC independently of a gaseous ligand, we conclude that stabilization of the enzyme's active configuration is the underlying mechanism of YC-1's action. Moreover, the results obtained with YC-1 reveal that CO is capable of stimulating sGC to a degree similar to NO, and thus provide the molecular basis for CO functioning as a signaling molecule.
Friebe
A
A
Institut für Pharmakologie, Freie Universität Berlin, Germany.
Schultz
G
G
Koesling
D
D
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D002417:Cattle; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
D011994:Recombinant Proteins; D002248:Carbon Monoxide; D006162:Guanylate Cyclase