Hydrogen sulfide (H2S) is a well-known toxic gas that has the smell of rotten eggs. This pungent gas was considered as a physiological mediator, after the identification of endogenous sulfides in the mammalian brain. H2S is produced from L-cysteine by enzymes such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase (CAT). We recently identified a fourth pathway, where H2S is produced from D-cysteine by the enzyme D-amino acid oxidase (DAO) along with 3MST. We demonstrated that H2S is a neuromodulator that facilitates hippocampal long-term potentiation (LTP) by enhancing the activity of N-methyl-D-aspartate (NMDA) receptors. It also induces Ca(2+) influx in the astrocytes by activating the transient receptor potential ankyrin-1 (TRPA1) channels. In addition to being a signaling molecule, it also functions as a neuroprotective agent by enhancing the production of glutathione, a major intracellular antioxidant that scavenges the reactive oxygen species (ROS) in the mitochondria. H2S regulates the activity of the enzymes by incorporating the bound sulfane sulfur to cysteine residues. This modification is known as sulfhydration or sulfuration. The neuroprotective ubiquitin E3 ligase, parkin, enhances its neuroprotective activity by this modification. This review is focused on the functional role of H2S as a signaling molecule and as a cytoprotectant in the nervous system. In addition, this review shows the recent findings that indicate that the H2S-derived polysulfides found in the brain activate TRPA1 channels more potently than parental H2S.
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