Mammalian nerve globins in search of functions

Ascenzi, Paolo; Gustincich, Stefano; Marino, Maria

doi:10.1002/iub.1267

Cited by 51 publications

(53 citation statements)

References 150 publications

(258 reference statements)

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“…However, the discovery of a second ER subtype in 437 1996 partially solved these ambiguities with the evidence that 438 each E2 cognate receptor subtype (i.e., ERa and ERb) could activate 439 divergent signal transduction pathways [32,43]. This discovery 440 unveiled the paradigm that the balance between ERa and ERb 441 levels and/or activities could drive E2-responsive cells to different [4,29,36,46,52,53,62]. Thus, NGB is a pro-472 survival antiapoptotic molecule for brain-derived tissues.…”

Section: Introductionmentioning

confidence: 94%

ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury

Fiocchetti

Camilli

Acconcia

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Introductionmentioning

confidence: 94%

ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury

Fiocchetti

Camilli

Acconcia

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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“…The suggested electrochemical approach is free from these complications and can be further used for more detailed studies of the affinity of NGB to bind O 2 or other gases in different conditions. Affinity to O 2 that is regulated through the disulfide bond is an intriguing feature of NGB but its role in O 2 supply/storage is unlikely for many reasons (3,4). The role of NGB as a possible NO dioxygenase is more supported because such a function is well known for hemoglobin, myoglobin, and especially for flavohemoglobin (61).…”

Section: Methodsmentioning

confidence: 99%

“…O 2 binding/supply, the metabolism of reactive nitrogen and oxygen species, apoptosis through different pathways, intracellular signaling, and cell protection during hypoxia and ischemia (1)(2)(3)(4)(5)(6). Besides the central and peripheral nervous system and retina, Ngb is also expressed in endocrine tissues, hematopoietic stem cells, the gastrointestinal tract, and cancer cells (7,8).…”

Section: Neuroglobin (Ngb)mentioning

confidence: 99%

Electrochemical Evidence for Neuroglobin Activity on NO at Physiological Concentrations

Trashin¹,

Jong²,

Luyckx

et al. 2016

Journal of Biological Chemistry

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The true function of neuroglobin (Ngb) and, particularly, human Ngb (NGB) has been under debate since its discovery 15 years ago. It has been expected to play a role in oxygen binding/ supply, but a variety of other functions have been put forward, including NO dioxygenase activity. However, in vitro studies that could unravel these potential roles have been hampered by the lack of an Ngb-specific reductase. In this work, we used electrochemical measurements to investigate the role of an intermittent internal disulfide bridge in determining NO oxidation kinetics at physiological NO concentrations. The use of a polarized electrode to efficiently interconvert the ferric (Fe 3؉ ) and ferrous (Fe 2؉ ) forms of an immobilized NGB showed that the disulfide bridge both defines the kinetics of NO dioxygenase activity and regulates appearance of the free ferrous deoxy-NGB, which is the redox active form of the protein in contrast to oxy-NGB. Our studies further identified a role for the distal histidine, interacting with the hexacoordinated iron atom of the heme, in oxidation kinetics. These findings may be relevant in vivo, for example, in blocking apoptosis by reduction of ferric cytochrome c, and gentle tuning of NO concentration in the tissues. Neuroglobin (Ngb)2 is the vertebrate globin that has been hypothesized to be involved in, e.g. O 2 binding/supply, the metabolism of reactive nitrogen and oxygen species, apoptosis through different pathways, intracellular signaling, and cell protection during hypoxia and ischemia (1-6). Besides the central and peripheral nervous system and retina, Ngb is also expressed in endocrine tissues, hematopoietic stem cells, the gastrointestinal tract, and cancer cells (7,8). Although the first publication on the subject was in 2000, the in vivo role of Ngb is still uncertain. Studies on Ngb knock-out mice and regional gene expression did not clarify it further (3, 9 -13), but most of the reports in the topic supported its neuroprotective function at least under conditions of neuroglobin overexpression (11,14,15). Some histological data additionally indicated that Ngb can be involved in regulation of the circadian rhythm (sleep-wake cycle) (12, 16) and protection of neurons from neurodegenerative disorders, such as Alzheimers disease (17)(18)(19). Obviously, further in vivo and in vitro studies of Ngb are necessary to clarify its molecular mechanisms of action.As other globins, e.g. myoglobin and hemoglobin, Ngb displays the three-over-three ␣-helical sandwich structure. However, Ngb structurally differs somewhat from myoglobin and hemoglobin, suggesting a different functional destination for Ngb compared with the classic globins (20). Both its weak O 2 binding affinity under physiological conditions (21) and its hexacoordinated structure of the iron atom of the heme leading to a possible intrinsic binding competition with external gaseous ligands such as O 2 , CO, and NO, support the hypothesis that Ngb is not constructed to transport or store O 2 (22). The unclear mechanism of actio...

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“…Although NGB is an O 2 -binding protein, the initial hypothesis that its protective role was to facilitate oxygen diffusion during periods of anoxia [25] has been challenged (see [58,64]) due to the low levels of the protein in the brain (<1 µM) and to the high O 2 binding rate but low O 2 dissociation rate of NGB [65,66,67]. However, although the biophysical properties of NGB are not optimal for oxygen transport, it has been suggested that the protein could actually play this physiological role at least in some district, as, for instance, in the retina [68].…”

Section: Possible Mechanisms Of Ngb Neuroprotectionmentioning

confidence: 99%

Neuroglobin, a Factor Playing for Nerve Cell Survival

Guidolin

Tortorella

Marcoli

et al. 2016

IJMS

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Cell death represents the final outcome of several pathological conditions of the central nervous system and available evidence suggests that in both acute injuries and neurodegenerative diseases it is often associated with mitochondrial dysfunction. Thus, the possibility to prevent mitochondrial events involved in cell death might represent efficient tools to limit neuronal damage. In recent years, increased attention has been paid to the endogenous protein neuroglobin, since accumulating evidence showed that its high expression was associated with preserved mitochondrial function and to an increased survival of nerve cells in vitro and in vivo in a variety of experimental models of cell insult. The biological and structural features of neuroglobin and the mitochondria-related mechanisms of neuroglobin-induced neuroprotection will be here briefly discussed. In this respect, the inhibition of the intrinsic pathway of apoptosis emerges as a key neuroprotective effect induced by the protein. These findings could open the possibility to develop efficient neuroglobin-mediated therapeutic strategies aimed at minimizing the neuronal cell death occurring in impacting neurological pathologies like stroke and neurodegenerative diseases.

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Mammalian nerve globins in search of functions

Cited by 51 publications

References 150 publications

ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury

ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury

Electrochemical Evidence for Neuroglobin Activity on NO at Physiological Concentrations

Neuroglobin, a Factor Playing for Nerve Cell Survival

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