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Signaling by Hydrogen Sulfide (H2S) and Polysulfides (H2sn) in The

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Signaling by Hydrogen Sulfide (H2S) and Polysulfides (H2sn) in The Neurochemistry International 126 (2019) 118–125 Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/neuint Signaling by hydrogen sulfide (H2S) and polysulfides (H2Sn) in the central nervous system T Hideo Kimura National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan ABSTRACT Hydrogen sulfide (H2S) is a signaling molecule used to modify neuronal transmission, regulate vascular tone, protect tissues from oxidative stress, sense oxygen, and generate ATP. Hydrogen polysulfides (H2Sn) have recently been identified as signaling molecules that mediate the activation of ion channels, regulation of tumor growth, and the transcriptional regulation of oxidative stress; some of which were previously ascribed to H2S. Cystathionine β-synthetase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) are known as H2S-producing enzymes. 3MST also produces H2Sn and other persulfurated molecules such as cysteine persulfide, glutathione persulfide, and persulfurated proteins. The chemical interaction of H2S and nitric oxide (NO) also produces H2Sn, which may be the mechanism underlying the synergistic effect of H2S and NO that was initially reported on vascular relaxation. H2Sn and other persulfurated molecules elicit their effect via S-sulfuration (S-sulfhydration) of specific cysteine residues of the target proteins. This review article focuses on the production and roles of H2Sn as well as H2S in the central nervous system. 1. Introduction 2013, 2015; Koike et al., 2017; Nagahara et al., 2018). Several other targets of H2Sn have been found; a tumor suppresser Memory loss is often observed in individuals exposed to toxic levels phosphatase and tensin homolog (PTEN) (Greiner et al., 2013), a of hydrogen sulfide (H2S), and the levels of neurotransmitters change in transcription factor complex consisting of Kelch ECH-associating pro- animals intoxicated with this molecule (Reiffenstein et al., 1992; tein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) com- Warenycia et al., 1989). The endogenous levels of H2S were evaluated plex that up-regulates antioxidant genes (Koike et al., 2013), a vascular in the brains of bovines, humans, and rats, though the levels were tension regulator protein kinase G1α (Stubbert et al., 2014), and gly- overestimated because of the method used (Goodwin et al., 1989; ceraldehyde-3-phosphate dehydrogenase (GAPDH), an enzyme that Warenycia et al., 1989; Savage and Gould, 1990; Ishigami et al., 2009). catalyzes glycolysis (Jarosz et al., 2015). They have been re-evaluated but still show significantly different values The chemical interaction of H2S and NO also generates H2Sn (Furne et al., 2008; Ishigami et al., 2009; Koike et al., 2017). H2Sis (EberhardtDux et al., 2014; Cortese-KrottKuhnle et al., 2015; Moustafa produced by cystathionine β-synthetase (CBS), cystathionine γ-lyase and Habara, 2016; Miyamoto et al., 2017). We identified synergy be- (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) in various tween H2S and nitric oxide (NO) during the relaxation of vascular tissues (Stipanuk and Beck, 1982; Abe and Kimura, 1996; Hosoki et al., smooth muscle (Hosoki et al., 1997), and a similar effect was observed 1997; Zhao et al., 2001; Shibuya et al., 2009; Chiku et al., 2009; Singh in the ileum (Teague et al., 2002). A mechanism of the synergy has been et al., 2009). studied, and several potential chemical entities generated from H2S and H2S facilitates the induction of hippocampal long-term potentiation NO have been proposed: nitrosothiol (Whiteman et al., 2006), thioni- (LTP) by enhancing the activity of N-methyl-D-aspartate (NMDA) re- trous acid (HSNO) (Filipovic et al., 2012), nitroxyl (HNO) ceptors (Abe and Kimura, 1996). In addition, we found that H2S acti- (EberhardtDux et al., 2014), nitrosopersulfide (SSNO-) (Cortese- vates transient receptor potential ankyrin 1 (TRPA1) channels in as- KrottKuhnle et al., 2015), and H2Sn (EberhardtDux et al., 2014; Cortese- trocytes, which regulate synaptic transmission by releasing KrottKuhnle et al., 2015; Moustafa and Habara, 2016; Miyamoto et al., gliotransmitters to the synaptic cleft to facilitate LTP induction (Nagai 2017). Concerning the characteristics of the product, such as the sen- et al., 2004; Oosumi et al., 2010; Shigetomi et al., 2012, 2013; Kimura sitivity to cyanide and reducing substances, H2Sn may be a potential et al., 2013). Subsequently, we identified H2Sn (n ≥ 2) which induce chemical entity that is produced from H2S and NO to activate TRPA1 2+ Ca influx in astrocytes more potently than H2S(Nagai et al., 2006; channels (EberhardtDux et al., 2014; Cortese-KrottKuhnle et al., 2015; Oosumi et al., 2010; Kimura et al., 2013). H2Sn are produced by 3MST, Miyamoto et al., 2017). and H2S2 and H2S3 have been identified in the brain (Kimura et al., H2S protects neurons from oxidative stress by enhancing the activity E-mail address: [email protected]. https://doi.org/10.1016/j.neuint.2019.01.027 Received 8 January 2019; Received in revised form 29 January 2019; Accepted 31 January 2019 Available online 06 March 2019 0197-0186/ © 2019 Elsevier Ltd. All rights reserved. H. Kimura Neurochemistry International 126 (2019) 118–125 of the cystine/glutamate antiporter and cysteine transporter to increase 3. S-sulfuration and bound sulfane sulfur the intracellular levels of cysteine, a substrate for the production of glutathione (GSH), a major intracellular antioxidant (Kimura and S-sulfuration (S-sulfhydration) was proposed by Snyder and col- Kimura, 2004). H2S also enhances the activity of glutamate cysteine leagues as a mode of action of H2S where H2S adds a sulfur atom to thiol ligase (GCL) also known as γ-glutamyl cysteine synthetase (γ-GCS), a of cysteine residues (R-Cys-SH) to make R-Cys-SSH (Mustafa et al., rate limiting enzyme for GSH production (Kimura and Kimura, 2004; 2009). However, this requires theoretical revision (Kimura, 2015). The Kimura et al., 2006, 2010). By these integrated effects, H2S increases oxidation state of sulfur in H2S and cysteine is −2 and atoms with the the production of GSH. same oxidation state do not react with each other. In contrast, the It has been reported that H2S also up- or down-regulates genes that oxidation state of sulfur in H2Sn is −1 or 0 and can S-sulfurate cysteine are activated by NMDA to induce excitotoxicity in neurons (Chen et al., residues. In contrast, under oxidative conditions some cysteine residues 2011). Although its mechanism is not well understood, the application are oxidized to become R-Cys-SOH, and at the exposure to NO, R-Cys- of H2S in diseases caused by oxidative stress may require the co-ad- SH is oxidized to R-Cys-SNO. Both R-Cys-SOH and R-Cys-SNO can be S- ministration of inhibitors of NMDA receptors to prevent excitotoxicity. sulfurated by H2S to R-Cys-SSH (Kabil et al., 2014). H2Sn also involved in the protection of neurons against oxidative Because Cys-SH has a pKa of 8.29 and the predicted pKa for Cys-SSH − + stress (Koike et al., 2013). H2S4 releases Nrf2 from the Keap1/Nrf2 is 4.34 (Cuevasanta et al., 2015), CysSSH dissociates to CysSS and H , complex so it can be transferred to the nucleus where Nrf2 upregulates while CysSH exists as non-dissociated form at physiological pH. S-sul- the transcription of antioxidant genes including enzymes involved in furation increases mass of 32 and adds one negative charge to the target the production of GSH. Recently, we demonstrated that sulfite (H2SO3) proteins. Compared to protein phosphorylation, which increases mass protects neurons from oxidative stress by potentially reacting with ex- of 95 and adds two negative charges, S-sulfuration may induce less tracellular cystine to generate cysteine that is more efficiently trans- conformational changes in target proteins. However, some of the ported into cells and used for GSH production (Kimura et al., 2018). known target proteins such as TRPA1 channels, PTEN, and protein ki- H2S and H2Sn may be involved in neurodegenerative diseases such nase G1α have two cysteine residues responsible for their activity as Parkinson's disease (PD), Huntington's diseases (HD), ethylmalonyl regulation. It is possible that one of the two cysteine residues could be encephalopathy, and even in cancer (Vandiver et al., 2013; Shiota et al., S-sulfurated and reacts with the remaining non-S-sulfurated cysteine 2018). Mutations encoded in the gene parkin cause hereditary PD. residue to produce a disulfide bond, which may induce greater con- Parkin of PD patients is nitrosylated, while that of healthy individuals is formational change than a simple S-sulfuration in TRPA1 channel and S-sulfurated (S-sulfhydrated) (Chung et al., 2004; Yao et al., 2004; PTEN and also enables two monomers of protein kinase G1α to gen- Vandiver et al., 2013). The expression of CSE in the brains of patients erate its dimer. with HD is significantly lower than that of normal individuals (Paul Bound sulfane sulfur, which is measured as H2S released from tis- et al., 2014). Patients with ethylmalonyl encephalopathy are defective sues or cells by reduction, includes H2Sn, Cys-SSH, GSSH, and S-sulfu- in ETHE1, persulfide dioxygenase, and are unable to metabolize H2S. rated cysteine residues (WarenyciaGoodwin et al., 1990; Ogasawara The increased levels of H2S exert its toxic effect on organs such as the et al., 1993, 1994; Ishigami et al., 2009; Shibuya et al., 2009). Cells brain and skeletal muscle (Tiranti et al., 2009). A recent study showed expressing 3MST contain greater levels of bound sulfane sulfur than that the higher concentrations of polysulfides including H2Sn are con- control cells (Shibuya et al., 2009), and oral administration of D-cy- tained in glioblastoma cells but not in glioblastoma-free control hemi- steine, which is metabolized by D-amino acid oxidase to 3-mercapto- spheres (Shiota et al., 2018). pyruvate a substrate of 3MST, is given to mice to increase the levels of bound sulfane sulfur (Shibuya et al., 2013).
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