Modes of physiologic H₂S Signaling in the brain and peripheral tissues

Significance: Hydrogen sulfide (H₂S), once associated with rotten eggs and sewers, is now recognized as a gasotransmitter that is synthesized in vivo in a regulated fashion. This ancient gaseous molecule has been retained throughout evolution to perform various roles in different life forms. H₂S modulates important signaling functions in diverse cellular processes ranging from regulation of blood pressure to redox homeostasis. Recent Advances: One of the modes by which H₂S signals is by post-translational modification of reactive cysteine residues in a process designated as sulfhydration, resulting in conversion of the -SH groups of target cysteine residues to -SSH. Using the modified biotin-switch assay and a fluorescent maleimide-based analysis, sulfhydration of several proteins has been detected in various cell types. Aberrant sulfhydration patterns occur in neurodegenerative conditions such as Parkinson's disease. Critical Issues: The exact concentration, source of H₂S, and conditions under which various stores of H₂S are utilized have not been fully elucidated. Currently, available inhibitors of the biosynthetic enzymes of H₂S lack sufficient specificity to shed light on detailed mechanisms of H₂S action. Probes with a higher sensitivity that can reliably detect cellular and tissue H₂S levels are yet to be developed. Future Directions: Availability of advanced probes and biosynthesis inhibitors would help in the measurement of real-time changes of endogenous H₂S levels in an in vivo context. The study of the dynamics of sulfhydration and nitrosylation of critical cysteine residues of regulatory proteins involved in physiology and pathophysiology is an area of interest for the future. Antioxid. Redox Signal. 22, 411-423.