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    Topic review

    Hydrogen Sulfide and Polysulfide Signaling

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    Submitted by: Hideo Kimura

    Definition

    We discovered H2S as a signaling molecule which is produced by enzymes to modulate the synaptic transmission and relax vasculature. The cytoprotective effect, anti-inflammatory activity, energy formation, and oxygen sensing by H2S have been subsequently demonstrated. Two additional pathways for the production of H2S with 3-mercaptopyruvate sulfurtransferase (3MST) from l- and d-cysteine have been identified. We also discovered that hydrogen polysulfides (H2Sn, n ≥ 2) are potential signaling molecules produced by 3MST. H2Sn regulate the activity of ion channels and enzymes, as well as even the growth of tumors. S-Sulfuration (S-sulfhydration) proposed by Snyder is the main mechanism for H2S/H2Sn underlying regulation of the activity of target proteins. 

    1. Identification of H2S as a Signaling Molecule

    Patients that recover from H2S poisoning show cognitive decline, and the levels of neurontransmitters in the brains of animals exposed to H2S change, suggesting that the brain is vulnerable to H2S toxicity [1]. Warenycia et al. measured the levels of H2S accumulated in the brain of rats exposed to H2S when they discovered a certain amount of H2S in the brain even without exposure to H2S [2]. Although the concentrations were overestimated, the existence of endogenous H2S was identified in the brain.
    Pyridoxal 5′-phosphate-dependent enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), have been suggested to regulate several pathways. CBS catalyzes the first step of the transsulfuration pathway in which cystathionine is produced from serine and homocysteine, and cystathionine is further catalyzed by CSE to cysteine. An alternate pathway exists in which CBS catalyzes the condensation of cysteine with homocysteine to generate cystathionine and H2S [3][4]. CSE catalyzes an elimination reaction which metabolizes cysteine to pyruvate, NH3, and H2S [3][4]. However, rather than being recognized as a physiologically active molecule, in these early studies, H2S was merely thought to be a byproduct of the metabolic pathways.
    The observations that H2S is produced by enzymes and exists in the brain prompted us to study a physiological role of this molecule. The activities of CBS and CSE have been intensively studied in the liver and kidney, but little is known about them in the brain. We found CBS in the brain and confirmed the production of H2S, which is augmented by S-adenosyl methionine (SAM) [5].
    Other gaseous signaling molecules NO and carbon monoxide (CO) induce hippocampal long-term potentiation (LTP), a synaptic model of memory formation, as retrograde messengers, which are produced at postsynapse and released to presynapse to facilitate a release of a neurotransmitter glutamate from presynapse [6][7][8][9][10]. We examined whether or not H2S has a similar effect. H2S facilitated the induction of LTP by enhancing the activity of N-methyl-d-aspartate (NMDA) receptors but not as a retrograde messenger [5].
    NMDA receptors are activated by a reducing substance dithiothreitol (DTT) through the reduction of a cysteine disulfide bond located at the hinge of the ligand-binding domain [11]. Because H2S is a reducing substance, it is likely to be a mechanism for facilitating the induction of LTP. However, H2S with one-tenth of the concentration of DTT exerted a greater effect than that of DTT [5]. This observation suggested that there is an additional mechanism for LTP induction by H2S. The prominent neuroscientist Solomon Snyder commented the following in Science News: “They have very impressive evidence that H2S is a potential neurotransmitter. It is an exciting paper that should stimulate a lot of people’s interest” [12].

    2. Identification of H2Sn as Signaling Molecules

    During this study, we found that a batch of NaHS, i.e., the sodium salt of H2S, with yellowish color was much more potent than the colorless batch. We successfully reproduced a solution with a similar color by dissolving elemental sulfur into Na2S solution according to a report by Searcy and Lee [13]. The color came from H2Sn, which induces Ca2+ influx in astrocytes much more potently than H2S [14][15][16]. H2Sn are natural inorganic polymeric sulfur–sulfur species or sulfane sulfur, which we later found to be produced by 3-mercaptopyruvate sulfurtransferase (3MST) from 3-mercaptopyruvate [17][18][19] and the partial oxidation of H2S [16], such as via the chemical interaction with NO [20][21]. H2S2 (2.6 µM) exists in the brain almost equivalent to the level of H2S (3 µM) [22]. Ca2+ influx induced in astrocytes by AITC, cinnamaldehyde, selective activators of TRPA1 channels, and Na2S3 was greatly suppressed by HC030031 and AP-18, selective inhibitors of TRPA1 channels. In astrocytes transfected with TRPA1-siRNA, Ca2+ influx was not efficiently induced by Na2S3 [16]. The EC50 value for H2S was 116 µM, while that for H2S3 was 91 nM, suggesting that H2Sn rather than H2S are ligands for TRPA1 channels [23][14][15][16]. The amino terminus of TRPA1 channels has 24 cysteine residues [24], and two cysteine residues Cys422 and Cys634 are sensitive to H2Sn [25].
    S-Sulfuration (S-sulfuhydration) was proposed by Snyder and colleagues to regulate the activity of target proteins by H2S [26]. This proposal needs a minor revision to highlight H2Sn but not H2S S-sulfurate cysteine residues. In contrast, H2S S-sulfurates oxidized cysteine residues such as those S-nitrosylated and S-sulfenylated [27]. H2Sn S-sulfurate (S-sulfhydrate) two cysteine residues of TRPA1 channels to induce the conformational changes to activate the channels. As an alternative mechanism, one cysteine residue, which is S-sulfurated, reacts with the remaining cysteine residue to generate a cysteine disulfide bond. Although the conformation has not been examined in detail, the latter mechanism may induce conformational changes more efficiently than the former one.

    3. Synergy and Crosstalk between H2S and NO

    H2S relaxes vascular smooth muscle in synergy with NO [28]. A similar result was also obtained in the ileum [29]. Whiteman et al. proposed that the chemical interaction of H2S with NO generate nitrosothiol, which releases NO in the presence of Cu2+ [30]. Filipovic et al. reported that H2S and NO produces nitroxyl (HNO) as a major product, as well as H2Sn [31][32], while Cortese-Krott et al. suggested that SSNO as a major product with H2Sn as a minor one [33]. We proposed that H2Sn are major products [20]. The effect of H2Sn and that of the products obtained from the mixture of Na2S and diethylamine NONOate, an NO donor, were eliminated when they were exposed to cyanide or DTT [20]. In contrast, HNO is resistant to cyanide, and SSNO is resistant to DTT. Based on these observations, H2Sn are potential chemical entities produced from H2S and NO [20][32][33]. Bogdandi et al. recently suggested that H2Sn transiently activate TRPA1 channels at the early phase of the production from H2S and NO, while the more stable product SSNO sustainably activates the channels [34].

    4. Vascular Tone Regulation by H2S and H2Sn

    Since H2S relaxes vascular smooth muscle in synergy with NO [28] and activates ATP-dependent K+ (KATP) channels [35], it has been suggested that H2S is a potential endothelial-derived hyperpolarizing factor (EDHF), which is a component of endothelial-derived relaxing factor (EDRF) [36]. However, previous studies showed that the hyperpolarization induced by EDHF is resistant to glibenclamide, a KATP channel blocker [37][38]. The relaxation of vascular smooth muscle in the mesenteric bed, which is mediated predominantly by EDHF, is rather abolished by apamine, a blocker of Ca2+-activated K+ channels [39].
    H2Sn are potential EDHFs (Figure 1). H2Sn produced by 3MST together with cysteine aminotransferase (CAT), both of which are localized to the vascular endothelium [17][40][41], or H2Sn generated by the chemical interaction between H2S and NO produced by endothelial NO synthase (eNOS) can activate TRPA1 channels [16][20] localized to myoendothelial junctions. The channels induce Ca2+ influx, which activate Ca2+-activated K+ channels to hyperpolarize the endothelial cell plasma membrane. The change in membrane potential is conducted via myoendothelial gap junctions to hyperpolarize the vascular smooth muscle [42].
    Figure 1. H2Sn are potential EDHFs. Both 3MST and eNOS are localized to endothelium. H2Sn produced by 3MST or by the chemical interaction between H2S and NO activate TRPA1 channels present in myoendothelial junctions to induce Ca2+ influx, which activates Ca2+-dependent K+ channels. The change in membrane potential is conducted via gap junction to hyperpolarize the smooth muscle plasma membrane.

    5. Cytoprotective Effect of H2S, H2Sn, and H2SO3

    The impression of H2S as toxic gas led to its cytoprotective effect being overlooked [43]. Expecting that all cells would be killed by H2S, I applied NaHS to cells and incubated for overnight. On the contrary, cells were lively and survived from the toxin. H2S increases the production of glutathione (GSH), a major intracellular antioxidant, by enhancing the activity of cystine/glutamate antiporter, which incorporates cystine into cells, and of glutamate cysteine ligase (GCL), a rate-limiting enzyme for GSH production [43][44]. H2S also facilitates the translocation of GSH into mitochondria [44]. The protective activity of H2S is also exerted through the stabilization of membrane potential by enhancing the activity of KATP channels and cystic fibrosys transmembrane conductance regulator (CFTR) Cl channels [45]. Lefer and colleagues demonstrated that H2S protects the heart from ischemia/reperfusion injury by preserving mitochondrial function [46].

    6. Signaling by H2S, H2Sn through S-Sulfuration and Bound Sulfane Sulfur

    In addition to CBS and CSE, 3MST, along with CAT or DAO, was recognized to produce H2S from l- or d-cysteine, respectively [41][47][48]. Subsequently, 3MST was found to produce H2Sn and other S-sulfurated molecules such as cysteine persulfide, GSSH, and S-sulfurated cysteine residues [17][18][49]. Other enzymes such as sulfide-quinone oxidoreductase (SQR), haemoglobin, neuroglobin, catalase, super oxide dismutase (SOD), cysteine tRNA synthetase (CARS), and peroxidases have been identified to produce H2Sn and other S-sulfurated molecules [50][51][52][53][54][55][56][57][58].
    In total, 10–20% of cysteine residues of proteins are S-sulfurated [26], also observed as a part of bound sulfane sulfur, which releases H2S under reducing conditions, including H2Sn, cysteine persulfide, GSSH, and S-sulfurated cysteine residues [59][60][61][62]. In cells and tissues, 5–12% of total protein cysteine residues are oxidized, such as S-nitrosylated (P-CysSNO) and S-sulfenylated (P-CysSOH), and this can be increased to more than 40% under oxidative conditions [63] (Figure 2). The amount of bound sulfane sulfur and its associated species is distinct among tissues. For example, heart homogenates release H2S under reducing conditions much less than those from the liver and the brain, while heart homogenates absorb H2S as fast as liver homogenates [62]. P-CysSNO and P-CysSOH react with H2S to generate P-CysSSH, while they do not release H2S under reducing conditions. These observations suggest that the heart may contain P-CysSNO and P-CysSOH more abundantly than the liver and the brain.
    Figure 2. S-Sulfuration of cysteine residues by H2S and H2Sn. Cysteine residues are S-sulfenylated by H2O2 and S-nitrosylated by NO. These oxidized cysteine residues are S-sulfurated by H2S. In contrast, cysteine residues are S-sulfurated by H2Sn.

    Some cysteine residues are oxidized by H2O2 to generate S-nitrosylated cysteine residues, and some others are S-nitrosylated by NO. These oxidized cysteine residues are S-sulfurated by H2S rather than H2Sn (Figure 2). Cys150 and Cys156 of GAPDH may be in the different oxidation state as described previously [26][64]. Zivanovic et al. demonstrated that the activity of manganese superoxide dismutase is suppressed through S-sulfenylation by H2O2, while the activity is recovered by H2S, which S-sulfurates the S-sulfenylated cysteine residues [65]. The same group showed that epidermal growth factor (EGF) activates its receptor in which the levels of S-sulfenylated cysteine residues are increased at the early phase, and those of S-sulfurated residues are increased at late phase when the expression of H2S producing enzymes is enhanced. H2S S-sulfurates those S-sulfenylated cysteine residues to regulate their activity (Figure 2).

    Another role of S-sulfuration is that it enables proteins to recover their functions from over-oxidization. Sulfinic (Protein-CysSO2H) and sulfonic acids (Protein-CysSO3H) are not reduced back to Protein-CysSH by thioredoxin and deteriorate the protein function. In contrast, S-sulfurated proteins P-CysSSO2H and P-CysSSO3H can be reduced by thioredoxin to P-CysSH [65][66].

    The entry is from 10.3390/biom11060896

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