Molecular Mechanism for H<sub>2</sub>S-Induced Activation of K<sub>ATP</sub>Channels

Jiang, Bo; Tang, Guanghua; Cao, Kun; Wu, Lingyun; Wang, Rui

doi:10.1089/ars.2009.2894

Cited by 186 publications

(137 citation statements)

References 51 publications

(59 reference statements)

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“…On the other hand, NaHS induced substantially greater vasodilation in CBS-null mice than in WT mice ( Fig. 2C), indicating that the vasodilatory machinery in CBS-null mice is intact and appears to display supersensitivity of H 2 S-responsive elements after depletion of endogenous H 2 S. Physiological vasodilation elicited by H 2 S is mediated by K ATP channels (21), the blockade of which by glibenclamide (100 μM) abolishes the effects of NaHS. Glibenclamide was seen to abolish CrMP-induced arteriolar vasodilation (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…The CO and NO systems interface; thus, the vasodilatory actions of HO inhibitors are partially reversed by inhibitors of NOS (14). A third gaseous mediator, H 2 S, is also vasoactive, eliciting vasodilation in both the peripheral and cerebral circulation (17)(18)(19)(20)(21). H 2 S can be physiologically generated by two enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE).…”

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confidence: 99%

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Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Morikawa

Kajimura

Nakamura

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

235

230

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Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H 2 S formed by cystathionine β-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H 2 S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2-null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia.gas biology | neurovascular unit | energy metabolism | gasotransmitter T he cerebral circulation is maintained by autoregulation, which prevents marked alterations in response to changes in blood pressure, whereas functional hyperemia links blood flow to neural activity (1). Blood flow regulation in the brain is modulated by O 2 (2), with increased cerebral blood flow in response to hypoxia critical for protecting the brain against diverse insults. Such regulation also participates in functional hyperemia, as demonstrated by functional MRI investigations indicating a transient decrease in O 2 levels preceding activation of blood flow in response to neuronal firing (3).Alterations in cerebral blood flow in response to hypoxia and neural activity are mediated via several neurotransmitter systems, with prominent involvement of the gaseous mediator nitric oxide (NO) (1, 2). In response to glutamate acting on NMDA receptors, neuronal NO synthase (nNOS) is activated by increases in intracellular calcium, with the generated NO stimulating soluble guanylyl cyclase, thereby increasing cGMP levels to dilate blood vessels (4). Functional hyperemia is decreased by ∼50% in rats in response to inhibition of nNOS (5). Another gaseous mediator, CO (6-8), is also vasoactive. In some blood vessel systems (e.g., liver sinusoids), CO causes vasodilation, and inhibition of its biosynthetic enzyme HO-2 leads to vasoconstriction (9-13). However, in the cerebral circulation, CO elicits vasoconstriction. Thus, HO inhibitors cause cerebral vasodilation, an effect reversed by CO (14). This action of CO cannot be readily explained by previously identified CO receptors, such as soluble guanylyl cyclase (6-12, 15) or potassium channels (13, 16), both of which mediate vasodilation. The CO and NO systems interface; thus, the vasodilatory actions of HO inhibitors are partially reversed by inhibitors of NOS (14). A third gaseous mediator, H 2 S, is also vasoactive, eliciting vasodilation in both the peripheral and cerebral circulation (17-21). H 2 S can be physiologically ...

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Section: Resultsmentioning

confidence: 93%

mentioning

confidence: 99%

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Morikawa

Kajimura

Nakamura

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

235

230

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“…Unlike sulfhydration, disulfide bonds readily reform when H 2 S is removed (196). H 2 S appears to use this mechanism to close K ATP channels by breaking disulfide bonds in the SUR subunit (65). In reaction 2 (above), the disulfide product, HSSH can also act as an oxidant and interact with other proteins (50).…”

Section: Olsonmentioning

confidence: 99%

Hydrogen sulfide as an oxygen sensor

Olson

2013

Clinical Chemistry and Laboratory Medicine

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Significance: Although oxygen (O 2 )-sensing cells and tissues have been known for decades, the identity of the O 2 -sensing mechanism has remained elusive. Evidence is accumulating that O 2 -dependent metabolism of hydrogen sulfide (H 2 S) is this enigmatic O 2 sensor. Recent Advances: The elucidation of biochemical pathways involved in H 2 S synthesis and metabolism have shown that reciprocal H 2 S/O 2 interactions have been inexorably linked throughout eukaryotic evolution; there are multiple foci by which O 2 controls H 2 S inactivation, and the effects of H 2 S on downstream signaling events are consistent with those activated by hypoxia. H 2 S-mediated O 2 sensing has been demonstrated in a variety of O 2 -sensing tissues in vertebrate cardiovascular and respiratory systems, including smooth muscle in systemic and respiratory blood vessels and airways, carotid body, adrenal medulla, and other peripheral as well as central chemoreceptors. Critical Issues: Information is now needed on the intracellular location and stoichometry of these signaling processes and how and which downstream effectors are activated by H 2 S and its metabolites. Future Directions: Development of specific inhibitors of H 2 S metabolism and effector activation as well as cellular organelle-targeted compounds that release H 2 S in a timeor environmentally controlled way will not only enhance our understanding of this signaling process but also provide direction for future therapeutic applications. Antioxid. Redox Signal. 22, 377-397.

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“…Among other functionally relevant Cys modifications are (i) a thioether bond with farnesyl or geranylgeranyl groups (leading to protein lipidation, and finally to membrane anchoring, 103), and (ii) mixed disulfide bonds with endogenous hydrogen sulfide (H 2 S). The latter modification has been linked to various physiological (22,46,100,101,102) and structural effects (45), revealing H 2 S as a potent signal molecule, and Cys as its amino acid target. …”

Section: Regulatory Cysmentioning

confidence: 99%

Redox Biology: Computational Approaches to the Investigation of Functional Cysteine Residues

Marino

Gladyshev

2011

Antioxidants & Redox Signaling

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Cysteine (Cys) residues serve many functions, such as catalysis, stabilization of protein structure through disulfides, metal binding, and regulation of protein function. Cys residues are also subject to numerous post-translational modifications. In recent years, various computational tools aiming at classifying and predicting different functional categories of Cys have been developed, particularly for structural and catalytic Cys. On the other hand, given complexity of the subject, bioinformatics approaches have been less successful for the investigation of regulatory Cys sites. In this review, we introduce different functional categories of Cys residues. For each category, an overview of state-of-the-art bioinformatics methods and tools is provided, along with examples of successful applications and potential limitations associated with each approach. Finally, we discuss Cys-based redox switches, which modify the view of distinct functional categories of Cys in proteins. Antioxid. Redox Signal. 15, 135-146.

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Molecular Mechanism for H₂S-Induced Activation of K_ATPChannels

Cited by 186 publications

References 51 publications

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Hydrogen sulfide as an oxygen sensor

Redox Biology: Computational Approaches to the Investigation of Functional Cysteine Residues

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Molecular Mechanism for H2S-Induced Activation of KATPChannels

Cited by 186 publications

References 51 publications

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Hydrogen sulfide as an oxygen sensor

Redox Biology: Computational Approaches to the Investigation of Functional Cysteine Residues

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Molecular Mechanism for H₂S-Induced Activation of K_ATPChannels