Hydrogen Sulfide (H(2)S) and Polysulfide (H(2)S(n)) Signaling: The First 25 Years

Since the first description of hydrogen sulfide (H(2)S) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on H(2)S have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous H(2)S in the brain, suggesting that H(2)S may have physiological roles. In 1996, we demonstrated that hydrogen sulfide (H(2)S) is a potential signaling molecule, which can be produced by cystathionine β-synthase (CBS) to modify neurotransmission in the brain. Subsequently, we showed that H(2)S 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 H(2)S and NO. The cytoprotective effect, anti-inflammatory activity, energy formation, and oxygen sensing by H(2)S have been subsequently demonstrated. Two additional pathways for the production of H(2)S with 3-mercaptopyruvate sulfurtransferase (3MST) from l- and d-cysteine have been identified. We also discovered that hydrogen polysulfides (H(2)S(n), n ≥ 2) are potential signaling molecules produced by 3MST. H(2)S(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 H(2)S/H(2)S(n) underlying regulation of the activity of target proteins. This mini review focuses on the key findings on H(2)S/H(2)S(n) signaling during the first 25 years.