Nitric oxide signaling pathways
Actions of NO can be cyclic guanosine monophosphate (cGMP)-dependent and cGMP-independent (mostly reactive nitrogen species-mediated) (Cordes et al., 2009[21]). The cGMP-dependent signaling pathway is the most important physiologic signaling pathway activated by NO (Pacher et al., 2007[97]; Omar et al., 2016[96]). In this pathway, only low concentrations of NO (5-10 nM) are required to activate guanylyl cyclase (GC) (Murad, 2006[91]; Pacher et al., 2007[97]), which converts guanosine triphosphate to cGMP (Murad, 2006[91]). Guanylyl cyclase has two isoforms: soluble (sGC is cytosolic) and membrane (particulate), of which, sGC is the receptor for NO (Murad, 2006[91]). Binding of two NO molecules is necessary for full activation of sGC; the first molecule binds to the β-subunit of sGC at picomolar affinity, partially activating it to ~15 % of its maximal activity (Horst and Marletta, 2018[54]); full activation of sGC depends on the NO concentration and occurs following binding of a second molecule of NO, which happens at nanomolar affinity; a conformational change in sGC following NO binding is the rate-limiting step for its activation; switching between partially and fully activated states is responsible for rapid activation and deactivation of sGC (Bahadoran et al., 2020[9]). The second site of sGC releases NO when cellular NO concentrations fall with the enzyme returning to its partially active state (Horst and Marletta, 2018[54]). Elevated cGMP levels activate the downstream elements of the NO signaling pathway (PKG, cGMP-gated cation channels and cGMP-regulated phosphodiesterases) and mediate its physiological actions (Gheibi et al., 2018[43], 2020[44]).
In addition to the NO/cGMP/PKG signaling pathway, nitrosative post-translational modifications such as S-nitrosylation, which is a reversible covalent attachment of NO to the cysteine residues of proteins, is a key mechanism for NO signaling (Crawford and Guo, 2005[22]; Berridge, 2014[13]). S-nitrosylation activates or inhibits protein function and therefore can be beneficial or detrimental (Wiseman and Thurmond, 2012[135]; Zheng et al., 2016[139]). Despite the presence of cysteine residues on almost all proteins and production of NO by most cells, only some proteins are nitrosylated (Mannick and Schonhoff, 2002[82]). The specificity of S-nitrosylation depends on the presence of metal ions (Mg2+ or Ca2+), local pH, and acid-base motifs (Altaany et al., 2014[4]).