National Institute of Neuroscience

Tokyo, Japan

National Institute of Neuroscience

Tokyo, Japan
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Kimura H.,National Institute of Neuroscience
Molecules | Year: 2014

Hydrogen sulfide (H2S) is recognized as a biological mediator with various roles such as neuromodulation, regulation of the vascular tone, cytoprotection, anti-inflammation, oxygen sensing, angiogenesis, and generation of mitochondrial energy. It is produced by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST). The activity of CBS is enhanced by S-adenosyl methionine (SAM) and glutathionylation, while it is inhibited by nitric oxide (NO) and carbon monoxide (CO). The activity of CSE and cysteine aminotransferase (CAT), which produces the 3MST substrate 3-mercaptopyruvate (3MP), is regulated by Ca2+. H2S is oxidized to thiosulfate in mitochondria through the sequential action of sulfide quinone oxidoreductase (SQR), sulfur dioxygenase, and rhodanese. The rates of the production and clearance of H2S determine its cellular concentration. Polysulfides (H2Sn) have been found to occur in the brain and activate transient receptor potential ankyrin 1 (TRPA1) channels, facilitate the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus, and suppress the activity of phosphatase and tensin homolog (PTEN) by sulfurating (sulfhydrating) the target cysteine residues. A cross talk between H2S and NO also plays an important role in cardioprotection as well as regulation of the vascular tone. H2S, polysulfides, and their cross talk with NO may mediate various physiological and pathophysiological responses. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


Kimura H.,National Institute of Neuroscience
Antioxidants and Redox Signaling | Year: 2010

Three hundred years have passed since the first description of the toxicity of hydrogen sulfide (H2S). Three papers in 1989 and 1990 described relatively high concentrations of sulfide in the brain. In 1996 we demonstrated that cystathionine β-synthase (CBS) is a H2S producing enzyme in the brain and that H2S enhances the activity of NMDA receptors and facilitates the induction of hippocampal long-term potentiation (LTP), a synaptic model of memory. In the following year, we demonstrated that another H2S producing enzyme, cystathionine γ-lyase is in the thoracic aorta, portal vein, and the ileum, and that H2S relaxes these tissues. Based on these observations we proposed H2S as a neuromodulator as well as a smooth muscle relaxant. We recently demonstrated that the third H2S-producing enzyme, 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase (CAT) produces H2S in the brain as well as in vascular endothelium. Various functions in many tissues have been proposed. H2S protects neurons and cardiac muscle from oxidative stress. H2S has pro- and anti-inflammatory effects, nociceptive effects, the regulatory function of insulin release, and is even involved in longevity. Recent progress in the studies of physiological functions of H2S in neurons and smooth muscle was described. Antioxid. Redox Signal. 12, 1111-1123. © 2010, Mary Ann Liebert, Inc.


Kimura H.,National Institute of Neuroscience
Antioxidants and Redox Signaling | Year: 2015

It has been almost two decades since the first demonstration of hydrogen sulfide (H2S) as a physiological mediator of cognitive function and vascular tone. H2S is physiologically important because it protects various organs from ischemia-reperfusion injury besides regulating inflammation, oxygen sensing, cell growth, and senescence. The production, metabolism, and regulation of H2S have been studied extensively. H2S modulates target proteins through sulfhydration (or sulfuration) or by the reduction of cysteine disulfide bonds. A large number of novel H2S-donating compounds are being developed owing to the therapeutic potential of H2S. Recently, polysulfides, rather than H2S, have been identified as molecules that sulfhydrate (or sulfurate) their target proteins. Antioxid. Redox Signal. 22, 347-349. © Copyright 2015, Mary Ann Liebert, Inc. 2015.


Kimura H.,National Institute of Neuroscience
Neurochemistry International | Year: 2013

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 Ca2+ 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. © 2013 Elsevier Ltd. All rights reserved.


Kimura H.,National Institute of Neuroscience
Amino Acids | Year: 2011

Hydrogen sulfide (H 2S), which is a well-known toxic gas, has been recognized as a signal molecule as well as a cytoprotectant. It is produced by three enzymes, cystathionine βsynthase, cystathionine γlyase and 3-mercaptopyruvate sulfurtransferase along with cysteine aminotransferase. In addition to an immediate release of H 2S from producing enzymes, it can be stored as bound sulfane sulfur, which may release H 2S in response to physiological stimuli. As a signal molecule, it modulates neuronal transmission, relaxes smooth muscle, regulates release of insulin and is involved in inflammation. Because of its reputation as a toxic gas, the function as a cytoprotectant has been overlooked: the nervous system and cardiovascular system are protected from oxidative stress. In this review, enzymatic production, release mechanism and functions of H 2S are focused on. © Springer-Verlag 2010.


Kimura H.,National Institute of Neuroscience
Antioxidants and Redox Signaling | Year: 2014

Significance: Hydrogen sulfide (H2S) has been recognized as a physiological mediator with a variety of functions. It regulates synaptic transmission, vascular tone, inflammation, transcription, and angiogenesis; protects cells from oxidative stress and ischemia-reperfusion injury; and promotes healing of ulcers. Recent Advances: In addition to cystathionine β-synthase and cystathionine γ-lyase, 3-mercaptopyruvate sulfurtransferase along with cysteine aminotransferase was recently demonstrated to produce H2S. Even in bacteria, H2S produced by these enzymes functions as a defense against antibiotics, suggesting that the cytoprotective effect of H2S is a universal defense mechanism in organisms from bacteria to mammals. Critical Issues: The functional form of H2S-undissociated H2S gas, dissociated HS ion, or some other form of sulfur-has not been identified. Future Directions: The regulation of H2S production by three enzymes may lead to the identification of the physiological signals that are required to release H2S. The identification of the physiological functions of other forms of sulfur may also help understand the biological significance of H2S. Antioxid. Redox Signal. 20, 783-793. © 2014, Mary Ann Liebert, Inc.


Kimura H.,National Institute of Neuroscience
Nitric Oxide - Biology and Chemistry | Year: 2014

Hydrogen sulfide (H2S) has been considered to be a physiological mediator since the identification of endogenous sulfides in the mammalian brain. H2S is produced from L-cysteine by enzymes such as cystathionine b-synthase (CBS), cystathionine c-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3MST), and cysteine aminotransferase (CAT). CSE and CAT are regulated by Ca2+.At steady-state low intracellular concentrations of Ca2+,CSE and the 3MST/CAT pathway produce H2S. However, after intracellular concentrations of Ca2+increase in stimulated cells, the production of H2S by these enzymes decreases. We recently identified a fourth pathway, by which H2S is produced from D-cysteine by the enzymes D-amino acid oxidase (DAO) and 3MST. This pathway is mainly localized in the cerebellum and the kidney. The production of H2S from D-cysteine is 80 times more efficient than that from L-cysteine in the kidney, and the administration of D-cysteine to mice ameliorates renal ischemia-reperfusion injury more effectively than L-cysteine. These results suggest that D-cysteine might be used to treat renal diseases or even increase the success of kidney transplantation. We found that H2S-derived polysulfides exist in the brain and activate transient receptor potential ankyrin-1 (TRPA1) channels 300 times more potently than H2S. Although TRPA1 channels mediate sensory transduction and respond to a variety of stimuli, including cold temperature, pungent compounds and environmental irritants, their endogenous ligand(s) has not been identified. The sulfane sulfur of polysulfides is a reactive electrophile that is readily transferred to a nucleophilic protein thiolate to generate the protein persulfide or bound sulfane sulfur by sulfhydration (as referred to as sulfuration). The bound sulfane sulfur-producing activity of polysulfides is much greater than that of H2S. This review focuses on the physiological roles of H2S and H2S-derived polysulfides as signaling molecules. © 2014 Elsevier Inc. All rights reserved.


Ichinohe N.,National Institute of Neuroscience
Frontiers in Neuroanatomy | Year: 2012

Structures associated with the small-scale module called minicolumn can be observed frequently in the cerebral cortex. However, the description of functional characteristics remains obscure. A significant confounding factor is the marked variability both in the def- inition of a minicolumn and in the diagnostic markers for identifying a minicolumn (see for review, Jones, 2000; DeFelipe et al., 2002; Rockland and Ichinohe, 2004). Within a minicol- umn, cell columns are easily visualized by conventional Nissl staining. Dendritic bundles were first discovered with Golgi methods, but are more easily seen with microtubule- associated protein 2 immunohistochemistry. Myelinated axon bundles can be seen by Tau immunohistochemistry or myelin staining. Axon bundles of double bouquet cell can be seen by calbindin immunohistochemistry. The spatial interrelationship among these mor- phological elements is more complex than expected and is neither clear nor unanimously agreed upon. In this review, I would like to focus first on the minicolumnar structure found in layers 1 and 2 of the rat granular retrosplenial cortex. This modular structure was first discovered as a combination of prominent apical dendritic bundles from layer 2 pyramidal neurons and spatially matched thalamocortical patchy inputs (Wyss et al., 1990). Further examination showed more intricate components of this modular structure, which will be reviewed in this paper. Second, the postnatal development of this structure and poten- tial molecular players for its formation will be reviewed. Thirdly, I will discuss how this modular organization is transformed in mutant rodents with a disorganized layer structure in the cerebral cortex (i.e., reeler mouse and shaking rat Kawasaki). Lastly, the potential significance of this type of module will be discussed. © 2012Ichinohe.


Kimura H.,National Institute of Neuroscience
Antioxidants and Redox Signaling | Year: 2015

Significance: Hydrogen sulfide (H2S) has been recognized as a signaling molecule as well as a cytoprotectant. It modulates neurotransmission, regulates vascular tone, and protects various tissues and organs, including neurons, the heart, and kidneys, from oxidative stress and ischemia-reperfusion injury. H2S is produced from l-cysteine by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase. Recent Advances: In addition to these enzymes, we recently identified a novel pathway to produce H2S from d-cysteine, which involves d-amino acid oxidase (DAO) along with 3MST. These enzymes are localized in the cytoplasm, mitochondria, and peroxisomes. However, some enzymes translocate to organelles under specific conditions. Moreover, H2S-derived potential signaling molecules such as polysulfides and HSNO have been identified. Critical Issues: The physiological stimulations, which trigger the production of H2S and its derivatives and maintain their local levels, remain unclear. Future Directions: Understanding the regulation of the H2S production and H2S-derived signaling molecules and the specific stimuli that induce their release will provide new insights into the biology of H2S and therapeutic development in diseases involving these substances. Antioxid. Redox Signal. 22, 362-376. © Copyright 2015, Mary Ann Liebert, Inc. 2015.


Kimura H.,National Institute of Neuroscience
Proceedings of the Japan Academy Series B: Physical and Biological Sciences | Year: 2015

Hydrogen sulfide (H2S) is a familiar toxic gas that smells of rotten eggs. After the identification of endogenous H2S in the mammalian brain two decades ago, studies of this molecule uncovered physiological roles in processes such as neuromodulation, vascular tone regulation, cytoprotection against oxidative stress, angiogenesis, anti-inflammation, and oxygen sensing. Enzymes that produce H2S, such as cystathionine β-synthase, cystathionine γ-lyase, and 3- mercaptopyruvate sulfurtransferase have been studied intensively and well characterized. Polysulfides, which have a higher number of inner sulfur atoms than that in H2S, were recently identified as potential signaling molecules that can activate ion channels, transcription factors, and tumor suppressors with greater potency than that of H2S. This article focuses on our contribution to the discovery of these molecules and their metabolic pathways and mechanisms of action. © 2015 The Japan Academy.

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