Significance: Soluble guanylyl cyclase (sGC), which produces the second messenger cyclic guanosine 3', 5'-monophosphate (cGMP), is at the crossroads of nitric oxide (NO) signaling: sGC catalytic activity is both stimulated by NO binding to the heme and inhibited by NO modification of its cysteine (Cys) thiols (S-nitrosation). Modulation of sGC activity by thiol oxidation makes sGC a therapeutic target for pathologies originating from oxidative or nitrosative stress. sGC has an unusually high percentage of Cys for a cytosolic protein, the majority solvent exposed and therefore accessible modulatory targets for biological and pathophysiological signaling. Recent Advances: Thiol oxidation of sGC contributes to the development of cardiovascular diseases by decreasing NO-dependent cGMP production and thereby vascular reactivity. This thiol-based resistance to NO (e.g., increase in peripheral resistance) is observed in hypertension and hyperaldosteronism.
Critical issues: Some roles of specific Cys thiols have been identified in vitro. So far, it has not been possible to pinpoint the roles of specific Cys of sGC in vivo and to investigate the molecular mechanisms in an animal model.
Future directions: The role of Cys as redox sensors, intermediates of activation, and mediators of change in sGC conformation, activity, and dimerization remains largely unexplored. To understand modulation of sGC activity, it is critical to investigate the roles of specific oxidative thiol modifications that are formed during these processes. Where the redox state of sGC thiols contribute to pathologies (vascular resistance and sGC desensitization by NO donors), it becomes crucial to design therapeutic strategies to restore sGC to its normal, physiological thiol redox state. Antioxid. Redox Signal. 26, 137-149.
Keywords: S-nitrosation; S-nitrosylation; guanylyl cyclase; nitric oxide; oxidative stress; reactive cysteine.