Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

H2S signalling through protein sulfhydration and beyond

Nature Reviews Molecular Cell Biology volume 13, pages 499–507 (2012)Cite this article

Subjects

Key Points

  • Hydrogen sulfide (H2S) has emerged as an important gasotransmitter and signalling molecule, akin to nitric oxide (NO) and carbon monoxide (CO).

  • H2S is generated from Cys and its derivatives by three enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MST).

  • H2S has a major role in vasorelaxation and regulation of blood pressure. Mice lacking CSE display substantial cardiovascular dysfunction and hypertension.

  • One of the mechanisms by which H2S mediates its effects is via protein sulfhydration, which is analogous to nitrosylation by NO. In the process of sulfhydration, the thiol group of a reactive Cys is modified to an persulfide (-SSH) group, resulting in increased reactivity of the Cys residue. Sulfhydration is more prevalent than nitrosylation, as 25–50% of murine hepatic proteins were found to be sulfhydrated.

  • Sulfhydration orchestrates diverse signalling pathways ranging from vasorelaxation to the stress response. The vasoactivity of H2S stems from its ability to sulfhydrate the Kir6.1 subunit of ATP-dependent potassium (KATP) channels to elicit hyperpolarization of vascular smooth muscle cells.

  • H2S regulates the endoplasmic reticulum (ER) stress response by sulfhydrating and inhibiting protein Tyr phosphatase 1B (PTP1B), a key player in the ER stress response pathway. H2S also mediates the anti-apoptotic activity of nuclear factor-κB (NF-κB) by sulfhydrating the p65 subunit, thereby augmenting the transcription of pro-survival genes.

  • Sulfhydration is a reversible event, a feature that is necessary for the dynamic regulation of signalling pathways.

  • Sulhydration and nitrosylation may interface to modulate cellular responses. In the case of stress signalling by NF-κB, sulfhydration of Cys38 precedes its nitrosylation, providing a mechanistic basis for differentiating cell survival from cell death.

Abstract

Hydrogen sulfide (H2S) has recently emerged as a mammalian gaseous messenger molecule, akin to nitric oxide and carbon monoxide. H2S is predominantly formed from Cys or its derivatives by the enzymes cystathionine β-synthase and cystathionine γ-lyase. One of the mechanisms by which H2S signals is by sulfhydration of reactive Cys residues in target proteins. Although analogous to protein nitrosylation, sulfhydration is substantially more prevalent and usually increases the catalytic activity of targeted proteins. Physiological actions of sulfhydration include the regulation of inflammation and endoplasmic reticulum stress signalling as well as of vascular tension.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hydrogen sulfide in stress signalling.
Figure 2: Mechanisms of hydrogen sulfide-induced vasodilation.

Similar content being viewed by others

References

  1. Stamler, J. S. et al. S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc. Natl Acad. Sci. USA 89, 444–448 (1992). The first study demonstrating protein S -nitrosylation on Cys residues both in vitro and in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Szabo, C. Roles of hydrogen sulfide in the pathogenesis of diabetes mellitus and its complications. Antioxid. Redox Signal. 17, 68–80 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Szabo, C. & Papapetropoulos, A. Hydrogen sulphide and angiogenesis: mechanisms and applications. Br. J. Pharmacol. 164, 853–865 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhu, X. Y., Gu, H. & Ni, X. Hydrogen sulfide in the endocrine and reproductive systems. Expert Rev. Clin. Pharmacol. 4, 75–82 (2011).

    CAS  PubMed  Google Scholar 

  5. Wang, R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol. Rev. 92, 791–896 (2012).

    CAS  PubMed  Google Scholar 

  6. Bredt, D. S. & Snyder, S. H. Nitric oxide: a physiologic messenger molecule. Annu. Rev. Biochem. 63, 175–195 (1994).

    CAS  PubMed  Google Scholar 

  7. Bredt, D. S. Nitric oxide signaling specificity — the heart of the problem. J. Cell Sci. 116, 9–15 (2003).

    CAS  PubMed  Google Scholar 

  8. Verma, A., Hirsch, D. J., Glatt, C. E., Ronnett, G. V. & Snyder, S. H. Carbon monoxide: a putative neural messenger. Science 259, 381–384 (1993).

    CAS  PubMed  Google Scholar 

  9. Zakhary, R. et al. Heme oxygenase 2: endothelial and neuronal localization and role in endothelium-dependent relaxation. Proc. Natl Acad. Sci. USA 93, 795–798 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Boehning, D. & Snyder, S. H. Novel neural modulators. Annu. Rev. Neurosci. 26, 105–131 (2003).

    CAS  PubMed  Google Scholar 

  11. Boehning, D., Sedaghat, L., Sedlak, T. W. & Snyder, S. H. Heme oxygenase-2 is activated by calcium-calmodulin. J. Biol. Chem. 279, 30927–30930 (2004).

    CAS  PubMed  Google Scholar 

  12. Stipanuk, M. H. & Beck, P. W. Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat. Biochem. J. 206, 267–277 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Shibuya, N., Mikami, Y., Kimura, Y., Nagahara, N. & Kimura, H. Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J. Biochem. 146, 623–626 (2009).

    CAS  PubMed  Google Scholar 

  14. Singh, S. & Banerjee, R. PLP-dependent H2S biogenesis. Biochim. Biophys. Acta 1814, 1518–1527 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Stipanuk, M. H. Metabolism of sulfur-containing amino acids. Annu. Rev. Nutr. 6, 179–209 (1986).

    CAS  PubMed  Google Scholar 

  16. Chen, X., Jhee, K. H. & Kruger, W. D. Production of the neuromodulator H2S by cystathionine β-synthase via the condensation of cysteine and homocysteine. J. Biol. Chem. 279, 52082–52086 (2004).

    CAS  PubMed  Google Scholar 

  17. Singh, S., Padovani, D., Leslie, R. A., Chiku, T. & Banerjee, R. Relative contributions of cystathionine β-synthase and γ-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. J. Biol. Chem. 284, 22457–22466 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Beard, R. S. Jr & Bearden, S. E. Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research. Am. J. Physiol. Heart Circ. Physiol. 300, H13–H26 (2011).

    CAS  PubMed  Google Scholar 

  19. Sen, U., Mishra, P. K., Tyagi, N. & Tyagi, S. C. Homocysteine to hydrogen sulfide or hypertension. Cell Biochem. Biophys. 57, 49–58 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Watanabe, M. et al. Mice deficient in cystathionine β-synthase: animal models for mild and severe homocyst(e)inemia. Proc. Natl Acad. Sci. USA 92, 1585–1589 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Taoka, S., Ohja, S., Shan, X., Kruger, W. D. & Banerjee, R. Evidence for heme-mediated redox regulation of human cystathionine β-synthase activity. J. Biol. Chem. 273, 25179–25184 (1998).

    CAS  PubMed  Google Scholar 

  22. Taoka, S., West, M. & Banerjee, R. Characterization of the heme and pyridoxal phosphate cofactors of human cystathionine β-synthase reveals nonequivalent active sites. Biochemistry 38, 2738–2744 (1999).

    CAS  PubMed  Google Scholar 

  23. Banerjee, R. & Zou, C. G. Redox regulation and reaction mechanism of human cystathionine-β-synthase: a PLP-dependent hemesensor protein. Arch. Biochem. Biophys. 433, 144–156 (2005).

    CAS  PubMed  Google Scholar 

  24. Shintani, T. et al. Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion. Hepatology 49, 141–150 (2009).

    CAS  PubMed  Google Scholar 

  25. Kabil, O. et al. Reversible heme-dependent regulation of human cystathionine β-synthase by a flavoprotein oxidoreductase. Biochemistry 50, 8261–8263 (2011).

    CAS  PubMed  Google Scholar 

  26. Finkelstein, J. D., Kyle, W. E., Martin, J. L. & Pick, A. M. Activation of cystathionine synthase by adenosylmethionine and adenosylethionine. Biochem. Biophys. Res. Commun. 66, 81–87 (1975).

    CAS  PubMed  Google Scholar 

  27. Abe, K. & Kimura, H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J. Neurosci. 16, 1066–1071 (1996). The first evidence for a functional role of H 2 S in the brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Hishiki, T. et al. Carbon monoxide: impact on remethylation/transsulfuration metabolism and its pathophysiologic implications. J. Mol. Med. (Berl.) 90, 245–254 (2012).

    CAS  Google Scholar 

  29. Chiku, T. et al. H2S biogenesis by human cystathionine γ-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J. Biol. Chem. 284, 11601–11612 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cavallini, D., Mondovi, B., De Marco, C. & Sciosciasantoro, A. Inhibitory effect of mercaptoethanol and hypotaurine on the desulfhydration of cysteine by cystathionase. Arch. Biochem. Biophys. 96, 456–457 (1962).

    CAS  PubMed  Google Scholar 

  31. Szczepkowski, T. W. & Wood, J. L. The cystathionase-rhodanese system. Biochim. Biophys. Acta 139, 469–748 (1967).

    CAS  PubMed  Google Scholar 

  32. Yang, G. et al. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase. Science 322, 587–590 (2008). The first study demonstrating a physiological role of H 2 S in vasorelaxation. This paper used CSE-deficient mice to establish that H 2 S is endogenously generated by CSE.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Diwakar, L. & Ravindranath, V. Inhibition of cystathionine-γ-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS. Neurochem. Int. 50, 418–426 (2007).

    CAS  PubMed  Google Scholar 

  34. Vitvitsky, V., Thomas, M., Ghorpade, A., Gendelman, H. E. & Banerjee, R. A functional transsulfuration pathway in the brain links to glutathione homeostasis. J. Biol. Chem. 281, 35785–35793 (2006).

    CAS  PubMed  Google Scholar 

  35. Linden, D. R. et al. Production of the gaseous signal molecule hydrogen sulfide in mouse tissues. J. Neurochem. 106, 1577–1585 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Morikawa, T. et al. Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway. Proc. Natl Acad. Sci. USA 109, 1293–1298 (2012). Demonstrates a crosstalk between the CO and H 2 S systems in regulation of cerebral vasodilation.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Enokido, Y. et al. Cystathionine β-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS. FASEB J. 19, 1854–1856 (2005).

    CAS  PubMed  Google Scholar 

  38. Lee, M., Schwab, C., Yu, S., McGeer, E. & McGeer, P. L. Astrocytes produce the antiinflammatory and neuroprotective agent hydrogen sulfide. Neurobiol. Aging 30, 1523–1534 (2009).

    CAS  PubMed  Google Scholar 

  39. Dombkowski, R. A., Russell, M. J. & Olson, K. R. Hydrogen sulfide as an endogenous regulator of vascular smooth muscle tone in trout. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R678–R685 (2004).

    CAS  PubMed  Google Scholar 

  40. Mathai, J. C. et al. No facilitator required for membrane transport of hydrogen sulfide. Proc. Natl Acad. Sci. USA 106, 16633–16638 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Czyzewski, B. K. & Wang, D. N. Identification and characterization of a bacterial hydrosulphide ion channel. Nature 483, 494–497 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Vitvitsky, V., Kabil, O. & Banerjee, R. High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations. Antioxid. Redox Signal. 17, 22–31 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Toohey, J. I. Sulfur signaling: is the agent sulfide or sulfane? Anal. Biochem. 413, 1–7 (2011).

    CAS  PubMed  Google Scholar 

  44. Pietri, R., Roman-Morales, E. & Lopez-Garriga, J. Hydrogen sulfide and hemeproteins: knowledge and mysteries. Antioxid. Redox Signal. 15, 393–404 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Weisiger, R. A., Pinkus, L. M. & Jakoby, W. B. Thiol S-methyltransferase: suggested role in detoxication of intestinal hydrogen sulfide. Biochem. Pharmacol. 29, 2885–7288 (1980).

    CAS  PubMed  Google Scholar 

  46. Levitt, M. D., Furne, J., Springfield, J., Suarez, F. & DeMaster, E. Detoxification of hydrogen sulfide and methanethiol in the cecal mucosa. J. Clin. Invest. 104, 1107–1114 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Olson, K. R. A. Practical look at the chemistry and biology of hydrogen sulfide. Antioxid. Redox Signal. 17, 32–44 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Siegel, L. M. A. Direct microdetermination for sulfide. Anal. Biochem. 11, 126–132 (1965).

    CAS  PubMed  Google Scholar 

  49. Levitt, M. D., Abdel-Rehim, M. S. & Furne, J. Free and acid-labile hydrogen sulfide concentrations in mouse tissues: anomalously high free hydrogen sulfide in aortic tissue. Antioxid. Redox Signal. 15, 373–378 (2011).

    CAS  PubMed  Google Scholar 

  50. Kraus, D. W. & Doeller, J. E. Sulfide consumption by mussel gill mitochondria is not strictly tied to oxygen reduction: measurements using a novel polarographic sulfide sensor. J. Exp. Biol. 207, 3667–3679 (2004).

    CAS  PubMed  Google Scholar 

  51. Kimura, H., Shibuya, N. & Kimura, Y. Hydrogen sulfide is a signaling molecule and a cytoprotectant. Antioxid. Redox Signal. 17, 45–57 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Jaffrey, S. R. & Snyder, S. H. The biotin switch method for the detection of S-nitrosylated proteins. Sci. STKE 2001, pl1 (2001).

    CAS  PubMed  Google Scholar 

  53. Jaffrey, S. R., Erdjument-Bromage, H., Ferris, C. D., Tempst, P. & Snyder, S. H. Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nature Cell Biol. 3, 193–197 (2001).

    CAS  PubMed  Google Scholar 

  54. Mustafa, A. K. et al. H2S signals through protein S-sulfhydration. Sci. Signal. 2, ra72 (2009). The first study demonstrating protein sulfhydration in vivo by using a CSE-deficient mice model.

    PubMed  PubMed Central  Google Scholar 

  55. Sen, N. et al. Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions. Mol. Cell 45, 13–24 (2012). Shows that pro-survival function of NF-κB is regulated by H 2 S, and introduces a new method using maleimide that can simultaneously measure sulfhydration and nitrosylation in the same sample.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Marino, S. M. & Gladyshev, V. N. Analysis and functional prediction of reactive cysteine residues. J. Biol. Chem. 287, 4419–4425 (2012).

    CAS  PubMed  Google Scholar 

  57. Poole, L. B. & Nelson, K. J. Discovering mechanisms of signaling-mediated cysteine oxidation. Curr. Opin. Chem. Biol. 12, 18–24 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Klomsiri, C., Karplus, P. A. & Poole, L. B. Cysteine-based redox switches in enzymes. Antioxid. Redox Signal. 14, 1065–1077 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Finkel, T. From sulfenylation to sulfhydration: what a thiolate needs to tolerate. Sci. Signal. 5, pe10 (2012).

    PubMed  Google Scholar 

  60. Krishnan, N., Fu, C., Pappin, D. J. & Tonks, N. K. H2S-induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response. Sci. Signal. 4, ra86 (2011). Links protein sulfhydration to ER stress signalling, and demonstrates that sulfhydration is reversible by the thioredoxin system.

    PubMed  PubMed Central  Google Scholar 

  61. Miller, D. L. & Roth, M. B. Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 104, 20618–20622 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Benhar, M., Forrester, M. T. & Stamler, J. S. Protein denitrosylation: enzymatic mechanisms and cellular functions. Nature Rev. Mol. Cell Biol. 10, 721–732 (2009).

    CAS  Google Scholar 

  63. Hara, M. R. et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nature Cell Biol. 7, 665–674 (2005).

    CAS  PubMed  Google Scholar 

  64. Sen, N. et al. Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nature Cell Biol. 10, 866–873 (2008).

    CAS  PubMed  Google Scholar 

  65. Shatalin, K., Shatalina, E., Mironov, A. & Nudler, E. H2S: a universal defense against antibiotics in bacteria. Science 334, 986–990 (2011). Demonstrates that H 2 S acts as a bacterial cytoprotectant, implying that inhibitors of its biogenesis may facilitate antibiotic therapy.

    CAS  PubMed  Google Scholar 

  66. Dickhout, J. G. et al. Integrated stress response modulates cellular redox state via induction of cystathionine γ-lyase: cross-talk between integrated stress response and thiol metabolism. J. Biol. Chem. 287, 7603–7614 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).

    CAS  PubMed  Google Scholar 

  68. Szabo, C. Hydrogen sulphide and its therapeutic potential. Nature Rev. Drug Discov. 6, 917–935 (2007).

    CAS  Google Scholar 

  69. Yang, G. Hydrogen sulfide in cell survival: a double-edged sword. Expert Rev. Clin. Pharmacol. 4, 33–47 (2011).

    CAS  PubMed  Google Scholar 

  70. Wallace, J. L., Caliendo, G., Santagada, V., Cirino, G. & Fiorucci, S. Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat. Gastroenterology 132, 261–271 (2007).

    CAS  PubMed  Google Scholar 

  71. Wallace, J. L. Hydrogen sulfide-releasing anti-inflammatory drugs. Trends Pharmacol. Sci. 28, 501–505 (2007).

    CAS  PubMed  Google Scholar 

  72. Moncada, S., Palmer, R. M. & Higgs, E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43, 109–142 (1991).

    CAS  PubMed  Google Scholar 

  73. Zakhary, R. et al. Targeted gene deletion of heme oxygenase 2 reveals neural role for carbon monoxide. Proc. Natl Acad. Sci. USA 94, 14848–14853 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Pollock, J. S. et al. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc. Natl Acad. Sci. USA 88, 10480–10484 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Mustafa, A. K. et al. Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. Circ. Res. 109, 1259–1268 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Edwards, G., Feletou, M. & Weston, A. H. Endothelium-derived hyperpolarising factors and associated pathways: a synopsis. Pflugers Arch. 459, 863–879 (2010).

    CAS  PubMed  Google Scholar 

  77. Wang, R. Hydrogen sulfide: a new EDRF. Kidney Int. 76, 700–704 (2009).

    CAS  PubMed  Google Scholar 

  78. Prabhakar, N. R. & Semenza, G. L. Gaseous messengers in oxygen sensing. J. Mol. Med. (Berl.) 90, 265–272 (2012).

    CAS  Google Scholar 

  79. Krueger, D. et al. Signaling mechanisms involved in the intestinal pro-secretory actions of hydrogen sulfide. Neurogastroenterol. Motil. 22, 1224–1231, e319–e320 (2010).

    CAS  PubMed  Google Scholar 

  80. Kohanski, M. A., Dwyer, D. J., Hayete, B., Lawrence, C. A. & Collins, J. J. A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130, 797–810 (2007).

    CAS  PubMed  Google Scholar 

  81. Fu, M. et al. Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. Proc. Natl Acad. Sci. USA 109, 2943–2948 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Francis, S. H. Busch, J.L., Corbin, J.D. & Sibley, D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol. Rev. 62, 525–563 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Xue, L. et al. Carbon monoxide and nitric oxide as coneurotransmitters in the enteric nervous system: evidence from genomic deletion of biosynthetic enzymes. Proc. Natl Acad. Sci. USA 97, 1851–1855 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Bucci, M. et al. Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity. Arterioscler. Thromb. Vasc. Biol. 30, 1998–2004 (2010).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work has been supported by United States Public Health Service Grants (MH018501) to S.H.S.

Author information

Authors and Affiliations

  1. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine.,

    Bindu D. Paul & Solomon H. Snyder

  2. Departments of Pharmacology and Psychiatry, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Solomon H. Snyder

Authors
  1. Bindu D. Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Solomon H. Snyder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Solomon H. Snyder.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Solomon H. Snyder's homepage

Glossary

Gasotransmitter

Endogenous gaseous molecule that can act as a messenger in signalling pathways.

Homocysteinaemia

A disorder that is characterized by increased homocysteine levels in the blood.

Astrocytes

Star-shaped glial cells of the central nervous system that form a structural and functional interface between non-nervous tissues and neurons.

Sulfane sulfur

The uncharged form of sulfur (SO), which is attached to proteins through a covalent bond between the SO atom and other sulfur atoms.

Amperometry

An electroanalytical technique that measures the current flow through an electrochemical cell. A constant fixed potential is applied to an electrochemical device (such as a sensor or electrode), and the current response, which reflects oxidation or reduction of analytes of interest, is monitored.

Biotin switch assay

An assay that detects nitrosylation of Cys residues by replacing the NO moiety with a detectable biotin derivative.

Acid dissociation constant

(pKa). A quantitative measure of the tendency of an acid to dissociate in solution. It is calculated as pKa = −log10Ka, in which Ka = [A−][H+]/[HA] and [A−], [H+] and [HA] are the concentration of the dissociated acid, protons and the undissociated (protonated) acid, respectively.

Thioredoxin system

Maintains the reducing environment in cells by facilitating electron transfer from NADPH through thioredoxin reductase to thioredoxin, which reduces its target proteins using highly conserved thiol groups.

Glyceraldehyde-3-phosphate dehydrogenase

(GAPDH). A glycolytic enzyme that catalyses the conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglyceric acid.

Endothelium-derived relaxing factors

(EDRFs). Factors derived from endothelial cells of blood vessels that can elicit vasorelaxation. Examples of EDRFs are NO, CO and H2S.

Cholinergic stimuli

Refers to molecules that are capable of activating acetylcholine receptors.

Muscarinic receptors

Acetylcholine G protein-coupled receptors that are activated by the prototypical agonist, muscarine, a compound isolated from the mushroom Amanita muscaria.

Calmodulin

A calcium protein that is found in all eukaryotes. Calmodulin has a high degree of structural conservation, can bind to target enzymes and modulate their activity as a function of cytosolic calcium concentration.

ATP-dependent potassium channels

(KATP channels). Potassium channels that are regulated by ATP. Binding of ATP keeps the channel in a closed conformation, preventing the entry of K+ ions.

Endothelium-derived hyperpolarizing factors

(EDHFs). Substances derived from the endothelium that act via ion channels to increase the electronegativity of the membrane.

Resistance blood vessels

Blood vessels that exhibit increased resistance to blood flow. Vascular resistance is directly proportional to the extent of vasoconstriction, which is one of the primary determinants of blood pressure.

Normoxic conditions

Ambient O2 concentrations (∼21%) or, in reference to tissue, O2 concentrations in normal physiological condition (∼2–3%).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paul, B., Snyder, S. H2S signalling through protein sulfhydration and beyond. Nat Rev Mol Cell Biol 13, 499–507 (2012). https://doi.org/10.1038/nrm3391

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3391

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing