Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H ₂ S) is now receiving increasing attention. Here we show that H ₂ S is physiologically generated by cystathionine γ-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H ₂ S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H ₂ S formation in response to vascular activation. These findings provide direct evidence that H ₂ S is a physiologic vasodilator and regulator of blood pressure.

The important life-supporting role of hydrogen sulfide (H₂S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H₂S had only been known for its toxicity and environmental hazard. Physiological importance of H₂S has been appreciated for about a decade. It started by the discovery of endogenous H₂S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H₂S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H₂S. The physiological functions of H₂S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H₂S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes, cirrhosis, inflammation, sepsis, neurodegenerative disease, erectile dysfunction, and asthma, to name a few. Many new technologies have been developed to detect endogenous H₂S production, and novel H₂S-delivery compounds have been invented to aid therapeutic intervention of diseases related to abnormal H₂S metabolism. While acknowledging the challenges ahead, research on H₂S physiology and medicine is entering an exponential exploration era.

Bearing the public image of a deadly “gas of rotten eggs,” hydrogen sulfide (H ₂ S) can be generated in many types of mammalian cells. Functionally, H ₂ S has been implicated in the induction of hippocampal long‐term potentiation, brain development, and blood pressure regulation. By acting specifically on K _ATP channels, H ₂ S can hyperpolarize cell membranes, relax smooth muscle cells, or decrease neuronal excitability. The endogenous metabolism and physiological functions of H ₂ S position this gas well in the novel family of endogenous gaseous transmitters, termed “gasotransmitters.” It is hypothesized that H ₂ S is the third endogenous signaling gasotransmitter, besides nitric oxide and carbon monoxide. This positioning of H ₂ S will open an exciting field‐H ₂ S physiology‐encompassing realization of the interaction of H ₂ S and other gasotransmitters, sulfurating modification of proteins, and the functional role of H ₂ Sin multiple systems. It may shed light on the pathogenesis of many diseases related to the abnormal metabolism of H ₂ S. — Wang, R. Two's company, three's a crowd: can H ₂ S be the third endogenous gaseous transmitter? FASEB J . 16, 1792–1798 (2002)

Hydrogen sulfide (H₂S), a messenger molecule generated by cystathionine γ-lyase, acts as a physiologic vasorelaxant. Mechanisms whereby H₂S signals have been elusive. We now show that H₂S physiologically modifies cysteines in a large number of proteins by S-sulfhydration. About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. Sulfhydration augments GAPDH activity and enhances actin polymerization. Sulfhydration thus appears to be a physiologic posttranslational modification for proteins.

Over the last decade, studies have unraveled many aspects of endogenous production and physiological functions of carbon monoxide (CO). The majority of endogenous CO is produced in a reaction catalyzed by the enzyme heme oxygenase (HO). Inducible HO (HO-1) and constitutive HO (HO-2) are mostly recognized for their roles in the oxidation of heme and production of CO and biliverdin, whereas the biological function of the third HO isoform, HO-3, is still unclear. The tissue type-specific distribution of these HO isoforms is largely linked to the specific biological actions of CO on different systems. CO functions as a signaling molecule in the neuronal system, involving the regulation of neurotransmitters and neuropeptide release, learning and memory, and odor response adaptation and many other neuronal activities. The vasorelaxant property and cardiac protection effect of CO have been documented. A plethora of studies have also shown the importance of the roles of CO in the immune, respiratory, reproductive, gastrointestinal, kidney, and liver systems. Our understanding of the cellular and molecular mechanisms that regulate the production and mediate the physiological actions of CO has greatly advanced. Many diseases, including neurodegenerations, hypertension, heart failure, and inflammation, have been linked to the abnormality in CO metabolism and function. Enhancement of endogenous CO production and direct delivery of exogenous CO have found their applications in many health research fields and clinical settings. Future studies will further clarify the gasotransmitter role of CO, provide insight into the pathogenic mechanisms of many CO abnormality-related diseases, and pave the way for innovative preventive and therapeutic strategies based on the physiologic effects of CO.