Modes of Physiologic H₂S Signaling in the Brain and Peripheral Tissues

Abstract

Significance: Hydrogen sulfide (H 2 S), 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. H 2 S 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 H 2 S 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 H 2 S, and conditions under which various stores of H 2 S are utilized have not been fully elucidated. Currently, available inhibitors of the biosynthetic enzymes of H 2 S lack sufficient specificity to shed light on detailed mechanisms of H 2 S action. Probes with a higher sensitivity that can reliably detect cellular and tissue H 2 S 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 H 2 S 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][412][413][414][415][416][417][418][419][420][421][422][423]

Protein kinase G–regulated production of H 2 S governs oxygen sensing

“…To delineate the mechanism by which CO inhibits CSE, we first considered whether CO inhibits calmodulin, a calcium-dependent activator of CSE (12). CO might inhibit CSE activity by reducing the pool of intracellular calcium available to stimulate calmodulin.…”

“…Emerging evidence suggests that CO suppresses H 2 S signaling by inhibiting the H 2 S-synthesizing enzymes cystathionine-γ-lyase (CSE) (7) and cystathionine β-synthase (CBS) (4, 6, 8, 9). CSE is the predominant source of H 2 S in peripheral tissues such as the carotid body (7, 10), whereas CBS is responsible for most of the H 2 S production in the brain (11, 12). It is believed that CO directly inhibits CBS by binding to its heme moiety (6, 8, 9).…”

Hydrogen sulfide in renal physiology, disease and transplantation – The smell of renal protection

“…Also, H2S is oxidized to polysulfides (H2Sn), that are more stable than H2S and in itself can act as signaling molecules. In fact, because of their oxidation state polysulfides are thought to be more potent to signal through sulfhydration than H2S [5,15,38].…”

Functional and Molecular Insights of Hydrogen Sulfide Signaling and Protein Sulfhydration

“…H2S also promote tumor growth by promoting angiogenesis and vasorelaxation [82]. Depletion of CBS can reverse H2S-mediated angiogenesis in colon cancer [83]. Taken together, these results indicate that CBS plays an important role in promoting angiogenesis and tumor growth.…”

“…H2S stimulates both processes and causes a reduction in inflammatory response [114]. Exposure to H2S also rendered macrophages hyporesponsive to inflammatory stimuli such as bacterial endotoxin or TNF-α [83]. Recently, it was shown that annexin- A1 serves as a pro-resolution mediator and H2S treatment facilitates this process by translocating annexin-A1 from cytosol to plasma membrane [83].…”