Hydrogen sulfide is a signaling molecule and a cytoprotectant

Abstract

Significance: Accumulating evidence shows that hydrogen sulfide may function as a signaling molecule in processes such as neuromodulation in the brain and smooth muscle relaxation in the vascular system. It also has a cytoprotective effect, since it can protect neurons and cardiac muscle from oxidative stress and ischemia-reperfusion injury, respectively. Hydrogen sulfide can also modulate inflammation, insulin release, and angiogenesis.

Recent advances: The regulation of the activity of 3-mercaptopyruvate sulfur transferase (3MST) along with cysteine aminotransferase (CAT), one of the H(2)S producing pathways, has been demonstrated. The production of H(2)S by the pathway, which is regulated by Ca(2+) and facilitated by thioredoxin and dihydrolipoic acid, is also involved in H(2)S signaling as well as cytoprotection. Sulfur hydration of proteins by H(2)S has been proposed to modulate protein functions. H(2)S-sensitive fluorescent probes, which enable us to measure the localization of H(2)S in real time, have been developed.

Critical issues: The basal concentrations of H(2)S have recently been measured and found to be much lower than those initially reported. However, the concentration of H(2)S reached in stimulated cells, as well as the regulation of H(2)S producing enzymes is not well understood. It has been proposed that some of the effects of H(2)S on the regulation of enzymes and receptors might be explained through the properties of sulfane sulfur (S(0)), another form of active sulfur.

Future directions: The determination of H(2)S concentrations in activated cells using new methods including H(2)S-sensitive fluorescent probes, as well as the investigation of the effects of H(2)S using specific inhibitors, may provide better understanding of the physiological function of this molecule. Clarifying mechanisms of H(2)S activity may also facilitate the development of new therapeutic compounds.

FIG. 1.

H₂S passes through the plasma membrane by diffusion. Aquaporin and anion channels are not required for H₂S and HS^- respectively to pass through the plasma membrane.

FIG. 2.

H₂S is released from the producing enzymes and bound sulfane sulfur. H₂S produced by enzymes may function as a signaling molecule and may also be stored in bound sulfane sulfur as intracellular stores. When cells are stimulated, H₂S can be released from the stores. Although lysates of neurons and astrocytes release H₂S in the presence of endogenous reducing substances, H₂S release from intact cells with physiological stimulations has not been fully elucidated. Which of the enzymatic production or the intracellular stores mainly contributes to the physiological release of H₂S has not been determined.

FIG. 3.

CBS is localized to astrocytes and 3MST to neurons in the brain. There is a reciprocal interaction between neurons and astrocytes. Neuronal excitation induces Ca²⁺ influx in astrocytes, which in turn regulate synaptic activity. H₂S produced by CBS in astrocytes may be involved in the induction of Ca²⁺ waves, which propagate to surrounding astrocytes and contribute to the signaling between astrocytes. H₂S generated by CBS in astrocytes and by 3MST in neurons may be involved in enhancing the activity of NMDA receptors and the synaptic activity.

FIG. 4.

Regulation of H₂S production by 3MST. Disulfides, such as thioredoxin (TRX) and dihydrolipoic acid (DHLA), are endogenous reducing substances, which can release H₂S from 3MST. The activity of CAT is regulated by Ca²⁺. In the absence of Ca²⁺, the production of H₂S by 3MST/CAT pathway from cysteine and α–ketoglutarate is the maximum but is suppressed by Ca²⁺ in a concentration-dependent manner.

FIG. 5.

A mechanism of releasing H₂S from 3MST in the presence of thioredoxin or DHLA. Thioredoxin and DHLA receive persulfide from 3MST. Thiol in thioredoxin and DHLA reduces persulfide to release H₂S.

FIG. 6.

Modulation of enzyme activity by phosphorylation and sulfurhydration. The reversible incorporation of sulfur into proteins may modulate protein function as phosphorylation does on proteins. H₂S may directly induce sulfurhydration. Alternatively, H₂S may react with oxygen to form S⁰ that adds to sulfhydryl groups of proteins.

FIG. 7.

The mechanisms for the induction of LTP. H₂S and nitric oxide (•NO) facilitate the induction of hippocampal long-term potentiation (LTP) with different mechanisms. •NO, which is produced from arginine, diffuses to presynapse to activate guanylyl cyclase, leading to the production of cyclic GMP that activates G-kinase to increase the release of a neurotransmitter glutamate. Although H₂S does not have any effect on guanylyl cyclase, it enhances the activity of NMDA receptors.

FIG. 8.

The sensitivity of astrocytes to H₂S depends on the state of maturation and reactivity. GFAP positive-mature astrocytes and those maturation-induced by leukemia inhibitory factor (LIF) respond well to H₂S. In contrast, premature astrocytes as well as reactive astrocytes induced by EGF, TGF-α, cAMP, and interleukin-1β do not respond to H₂S.