Hydrogen Sulfide (H₂S) and Polysulfide (H₂S_n) Signaling: The First 25 Years

Since the first description of hydrogen sulfide (H₂S) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on H₂S have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous H₂S in the brain, suggesting that H₂S may have physiological roles. In 1996, we demonstrated that hydrogen sulfide (H₂S) is a potential signaling molecule, which can be produced by cystathionine β-synthase (CBS) to modify neurotransmission in the brain. Subsequently, we showed that H₂S relaxes vascular smooth muscle in synergy with nitric oxide (NO) and that cystathionine γ-lyase (CSE) is another producing enzyme. This study also opened up a new research area of a crosstalk between H₂S and NO. 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 (H₂S_n, n ≥ 2) are potential signaling molecules produced by 3MST. H₂S_n 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/H₂S_n underlying regulation of the activity of target proteins. This mini review focuses on the key findings on H₂S/H₂S_n signaling during the first 25 years.