S-nitrosylation and the interaction between H2S and NO
For S-nitrosylation two mechanisms have been proposed. NO was initially thought only to diffuse after being produced by NO synthase (NOS) to the target proteins to S-nitrosylate them (Lancaster, 2017). However, it has been demonstrated that S-nitrosylation proceeds by clusters of enzymes which generate NO, synthesize S-nitrosylated proteins, and transnitrosylate it (Seth et al., 2018). Signaling by H2S, H2Sn and NO as well as S-sulfuration and S-nitrosylation must have both diffusion mediated- and enzyme oriented- mechanisms for regulating the activity of targets.
Synergistic effect of H2S with NO on vascular relaxation led to the identification of two mechanisms (Hosoki et al., 1997). One is that the chemical interaction between H2S and NO produces H2Sn, nitosothiol, thionitrous acid (HSNO), and nitrosopersulfide (HSSNO) that have the relaxation effect greater than each parental molecule (Nagai et al., 2006; Whiteman et al, 2006; Oosumi et al., 2010; Filipovic et al., 2012; Ebenhardt et al, 2014; Stubbert et al., 2014; Cortese-Krott et al., 2015; Moustafa and Habara, 2016; Miyamoto et al., 2017; See also Kimura, 2020). Another mechanism is that H2S and NO mutually regulate their synthesizing enzymes (Zhao et al., 2001; Minamishima et al., 2009; Kondo et al., 2013; King et al., 2014; Kimura, 2016). For chemical interaction between H2S and NO, both molecules should diffuse to interact with each other.
After the identification of EDRF as NO, there appeared a discrepancy. EDRF hyperpolarizes the membrane of vascular smooth muscle, while NO has little hyperpolarizing effect. Based on this observation it has been suggested that EDRF contains an additional factor, endothelium-derived hyperpolarizing factor (EDHF) (Chen et al., 1988). Because H2S activates KATP channels and hyperpolarizes the membrane potential, it has been proposed as a potential EDHF (Hosoki et al., 1997; Zhuo et al., 2001; Mustafa et al., 2011). Another possibility is H2Sn, which are produced by the chemical interaction of H2S with NO and activate protein kinase G1α (PKG1α) to relax vasculature, are also potent substances to activate KATP channels by S-sulfurating the active cysteine residue (Nagai et al., 2006; Whiteman et al, 2006; Oosumi et al., 2010; Mustafa et al., 2011; Filipovic et al., 2012; Ebenhardt et al, 2014; Stubbert et al., 2014; Cortese-Krott et al., 2015; Moustafa and Habara, 2016; Miyamoto et al., 2017; See also Kimura, 2020).