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PubMed2005

Effects of short-term hypoxia on neuroglobin levels and localization in mouse brain tissues.

Nerve cells are highly susceptible to ischemic and hypoxic injuries. The neuroglobin (Ngb), found in vertebrate nerve cells, has been suggested to protect nerve cells from ischemic episodes by a yet unknown mechanism. However, contradicting reports exist regarding localization and up-regulation of Ngb in response to hypoxia. The aim of the present study was to probe the distribution of Ngb proteins in mouse brain and retina by immunohistochemistry, and to quantify the levels of Ngb mRNA by reverse-transcription-polymerase chain reaction (RT-PCR) after short-term (2 h) exposure to 7.6% oxygen. We found Ngb to be present throughout the neocortex, most abundantly in the perirhinal, entorhinal and temporal cortical areas, the thalamus and hypothalamus, the choroid plexus, the olfactory bulb and the cranial nerve nuclei in the brainstem. Intense staining was observed in the mesencephalic central grey area and the Purkinje cells. Two-hour hypoxic exposure caused no detectable changes in staining intensity or spatial distribution of Ngb neither in the Purkinje cells nor in any other brain areas observed. The RT-PCR data supported the lack of differences in brain Ngb levels between normal and oxygen-deprived animals. In the retina, Ngb localization by immunohistochemistry was confined to the inner segments of the photoreceptors, the plexiform layers and the ganglion cells. Short-termed hypoxia did not change retinal Ngb levels as assessed by both techniques. The lack of Ngb up-regulation in the brain is consistent with results from previous long-term hypoxic experiments, suggesting that Ngb is not regulated by pure hypoxia in vivo.

Animals↗
PubMed2006

Neuroglobin and cytoglobin: oxygen-binding proteins in retinal neurons.

PURPOSE: The goal of this study was to describe the detailed localization of the novel oxygen-binding molecules, neuroglobin (Ngb) and cytoglobin (Cygb), in mammalian retinas and to determine whether Ngb and Cygb are neuronal or glial proteins in the retina. METHODS: Antibodies directed against Ngb and Cygb were used to examine their patterns of distribution in normal canine retinas. Immunoblot analysis was performed to verify antibody specificity and the presence of Ngb and Cygb in canine tissues. Double-labeling immunohistochemistry was performed with the Ngb and Cygb antibodies along with antibodies against neuronal (MAP-2, class III beta-tubulin (TUJ1), PKCalpha, and calretinin) and glial antigens (vimentin and CRALBP). Tissue sections were analyzed with light and confocal microscopy. RESULTS: Ngb and Cygb proteins were observed in different retinal cells. Cygb (but not Ngb) was also present in canine kidney, liver, lung, and heart tissue. Immunohistochemical analysis of canine retinas demonstrated Ngb immunoreactivity (IR) in the ganglion cell layer (GCL), inner (INL) and outer (ONL) nuclear layers, inner (IPL) and outer plexiform (OPL) layers, photoreceptor inner segments (IS), and retinal pigment epithelium (RPE). Ngb IR was localized within retinal neurons, but not in glia. Cygb IR was found in neurons and their processes in the GCL, IPL, INL, and OPL and within the RPE, but not in glia. CONCLUSIONS: Ngb and Cygb are widely distributed in retinal neurons and RPE, but not in glial cells of the canine retina. Their structure and distribution is suggestive of a possible role in oxygen transport in the mammalian retina.

Animals↗
PubMed2005

Possible neuroprotective mechanism of human neuroglobin.

Neuroglobin (Ngb) is a newly discovered hexacoordinate globin that is expressed in vertebrate brain and can reversibly bind oxygen. Expression of Ngb increases in response to oxygen deprivation and protects neurons from hypoxia in vitro and in vivo. Recent work on human Ngb has shed light on the mechanism of this neuroprotection by human Ngb, as discussed in this review. Human ferric Ngb has been found to act as a guanine nucleotide dissociation inhibitor for the alpha subunit of heterotrimeric G proteins. Moreover, other Ngb-binding proteins also have been identified. These findings suggest that human Ngb may function as a regulator of signal transduction in the brain.

Binding Sites↗
PubMed2004

Neuroglobin and other hexacoordinated hemoglobins show a weak temperature dependence of oxygen binding.

Mouse and human neuroglobins, as well as the hemoglobins from Drosophila melanogaster and Arabidopsis thaliana, were recombinantly expressed in Escherichia coli, and their ligand-binding properties were studied versus temperature. These globins have a common feature of being hexacoordinated (via the distal histidine) under deoxy conditions, as evidenced by a large amplitude for the alpha absorption band at 560 nm and the Soret band at 426 nm. The transition from the hexacoordinated form to the CO bound species is slow, as expected for a replacement reaction Fe-His --> Fe --> FeCO. The intrinsic binding rates would indicate a high oxygen affinity for the pentacoordinated form, due to rapid association and slow (100 ms-1 s) dissociation. However, the competing protein ligand results in a much lower affinity, on the order of magnitude of 1 torr. In addition to decreasing the affinity for external ligand, the competitive internal ligand leads to a weaker observed temperature dependence of the ligand affinity, since the difference in equilibrium energy for the two ligands is much lower than that of ligand binding to pentacoordinated hemoglobin. This effect could be of biological relevance for certain organisms, since it could provide a globin with an oxygen affinity that is nearly independent of temperature.

Animals↗
PubMed2001

[Coding region cDNA sequence cloning of rat neuroglobin gene, its polymorphism feature and tissue expression profile analysis].

The coding region cDNA sequence of rat neuroglobin (NGB) was obtained by RT-PCR technique using a degeneracy PCR primer pair based on previously reported cDNA sequence of human and mouse NGB gene. Result demonstrated that the coding region cDNA sequence of rat NGB gene is 456 bp in length, which could encode a protein of 151 amino acids. The rat NGB gene is highly homology with mouse (96%) and human (88%) NGB gene. However, several polymorphism sites were also detected in the rat NGB coding region: 113 t/c [L38P], 133 a/g [N45D], 388 a/g[R130G], 417 t/c. The cDNA sequence of rat NGB gene has been registered in GenBank under the accession number AF333245. Moreover, highly expression level of rat NGB in brain, liver, kidney, heart and skeletal muscle was detected by using multiple tissue RT-PCR technique, indicating the functional importance of this novel gene.

Amino Acid Sequence↗
PubMed2005

Effects of neuroglobin gene transfer in vivo on hearing response properties of neurons in the inferior colliculus in mice after administration of sodium salicylate.

The effects of neuroglobin (NGB) gene transfer in vivo mediated by GeneJamer on the hearing response properties of the inferior colliculus (IC) neurons in mice after administration of sodium salicylate were studied. Forty-eight Kunming mice were divided into 4 groups (n=12 in each group): Group A1 (negative control);Group A2 (positive control);Group B, sodium salicylate (450 mg/kg every day) + pEGFP-C1;Group C, sodium salicylate (450 mg/kg every day) + pEGFP-NGB. The GeneJamer and pEGFP-NGB were mixed and injected into IC neurons in mice. The expression of NGB mRNA and protein of IC neurons in mice was detected by using RT-PCR and Western blot methods. The intensity-rate functions, intensity-latency functions and frequency-turning curves in IC neurons were recorded by extracellular electrophysiological recording techniques and the effects of pEGFP-NGB transfer following injection of sodium salicylate on them were studied. It was found that: (1) The GeneJamer-mediated pEGFP-NGB could be effectively transferred into the IC brain tissues in mice and NGB could be expressed intensively. (2) The intensity-rate functions of IC neurons were raised after administration of sodium salicylate. The non-monotonic styles of intensity-rate functions in groups A1, A2 and C were accounted for 74.6%, 72.2 %, 59.3 %, respectively, and the function in group B for 47%. There were significant differences between group B and groups A1, A2 or C (P<0.01, P<0.01, P<0.05). (3) The intensity-latency functions in IC neurons were reduced after administration of sodium salicylate. The non-monotonic styles of intensity-latency functions in groups A1, A2 and C were accounted for 3.2 %, 5.1 %and 21 %, respectively, and that in group B for 45.5 %. There were significant differences between group B and groups A1, A2 or C (P<0.01, P<0.01, P<0.05, respectively). (4) The frequency-turning curves in groups A1 and A2 were sharpened. In 72 acoustic neurons recorded in the group B, the frequency-turning curves from 53 neurons were broadened while those of the rest were sharpened. In group C the frequency-turning curves recorded from 12 of 67 acoustic neurons were broadened while those of the remaining were sharpened. These results suggest that in vivo transfer of NGB gene is highly expressed in IC neurons in mice. In vivo transfer of NGB gene reverses the change of intensity-rate functions, intensity-latency functions and the code styles after administration of sodium salicylate in IC neurons in mice.

Journal Article↗
PubMed2006

The heme environment of mouse neuroglobin: histidine imidazole plane orientations obtained from solution NMR and EPR spectroscopy as compared with X-ray crystallography.

The 1H NMR chemical shifts of the heme methyl groups of the ferriheme complex of metneuroglobin (Du et al. in J. Am. Chem. Soc. 125:8080-8081, 2003) predict orientations of the axial histidine ligands (Shokhirev and Walker in J. Biol. Inorg. Chem. 3:581-594, 1998) that are not consistent with the X-ray data (Vallone et al. in Proteins Struct. Funct. Bioinf. 56:85-94, 2004), and the EPR spectrum (Vinck et al. in J. Am. Chem. Soc. 126:4516-4517, 2004) is only marginally consistent with these data. The reasons for these inconsistencies appear to be rooted in the high degree of aqueous solution exposure of the heme group and the fact that there are no strong hydrogen-bond acceptors for the histidine imidazole N-H protons provided by the protein. Similar inconsistencies may exist for other water-soluble heme proteins, and 1H NMR spectroscopy provides a simple means to verify whether the solution structure of the heme center is the same as or different from that in the crystalline state.

Animals↗
PubMed2002

From King George to neuroglobin: the psychiatric aspects of acute intermittent porphyria.

The porphyrias are a heterogeneous group of inherited deficiencies in the heme biosynthetic pathway. Acute intermittent porphyria is both the most prevalent and most severe form of this illness. Psychiatric symptoms are part of the classic presentation of this disorder, and psychiatric patients have a higher rate of porphyria than the general population. Despite this, clinicians often fail to consider this diagnosis in the differential for recalcitrant psychosis or depression. Many patients are asymptomatic until exposed to certain medications, liver damage, or hormonal changes. Diagnosis requires a high index of suspicion and a thorough history, physical examination, and laboratory evaluation. The author reviews historical aspects, diagnostic features, and optimal treatment of acute intermittent porphyria, considers possible etiologies of its psychiatric symptoms, and provides two case histories as examples.

Journal Article↗
PubMed2006

A globin for the brain.

The discovery that a myoglobin-like hemeprotein (called neuroglobin) is expressed in our brain raised considerable curiosity from the standpoints of biochemistry and pathophysiology alike. Neuroglobin is involved in neuroprotection from damage due to hypoxia or ischemia in vitro and in vivo; overexpression of neuroglobin ameliorates the recovery from stroke in experimental animals. The mechanism underlying this remarkable effect is still mysterious. Structural studies revealed that neuroglobin has a typical globin fold, and despite being hexacoordinated, it binds reversibly O2, CO, and NO, undergoing a substantial conformational change of the heme and of the protein. The possible mechanisms involved in neuroprotection are briefly reviewed. Neuroglobin is unlikely to be involved in O2 transport (like myoglobin), although it seems to act as a sensor of the O2/NO ratio in the cell, possibly regulating the GDP/GTP exchange rate forming a specific complex with the G(alpha beta gamma)-protein when oxidized but not when bound to a gaseous ligand. Thus it appears that neuroglobin is a stress-responsive sensor for signal transduction in the brain, mediated by a ligand-linked conformational change of the protein.

Animals↗
PubMed2000

A vertebrate globin expressed in the brain.

Haemoglobins and myoglobins constitute related protein families that function in oxygen transport and storage in humans and other vertebrates. Here we report the identification of a third globin type in man and mouse. This protein is predominantly expressed in the brain, and therefore we have called it neuroglobin. Mouse neuroglobin is a monomer with a high oxygen affinity (half saturation pressure, P50 approximately 2 torr). Analogous to myoglobin, neuroglobin may increase the availability of oxygen to brain tissue. The human neuroglobin gene (NGB), located on chromosome 14q24, has a unique exon-intron structure. Neuroglobin represents a distinct protein family that diverged early in metazoan evolution, probably before the Protostomia/Deuterostomia split.

Amino Acid Sequence↗
PubMed2004

A globin gene of ancient evolutionary origin in lower vertebrates: evidence for two distinct globin families in animals.

Hemoglobin, myoglobin, neuroglobin, and cytoglobin are four types of vertebrate globins with distinct tissue distributions and functions. Here, we report the identification of a fifth and novel globin gene from fish and amphibians, which has apparently been lost in the evolution of higher vertebrates (Amniota). Because its function is presently unknown, we tentatively call it globin X (GbX). Globin X sequences were obtained from three fish species, the zebrafish Danio rerio, the goldfish Carassius auratus, and the pufferfish Tetraodon nigroviridis, and the clawed frog Silurana tropicalis. Globin X sequences are distinct from vertebrate hemoglobins, myoglobins, neuroglobins, and cytoglobins. Globin X displays the highest identity scores with neuroglobin (approximately 26% to 35%), although it is not a neuronal protein, as revealed by RT-PCR experiments on goldfish RNA from various tissues. The distal ligand-binding and the proximal heme-binding histidines (E7 and F8), as well as the conserved phenylalanine CD1 are present in the globin X sequences, but because of extensions at the N-terminal and C-terminal, the globin X proteins are longer than the typical eight alpha-helical globins and comprise about 200 amino acids. In addition to the conserved globin introns at helix positions B12.2 and G7.0, the globin X genes contain two introns in E10.2 and H10.0. The intron in E10.2 is shifted by 1 bp in respect to the vertebrate neuroglobin gene (E11.0), providing possible evidence for an intron sliding event. Phylogenetic analyses confirm an ancient evolutionary relationship of globin X with neuroglobin and suggest the existence of two distinct globin types in the last common ancestor of Protostomia and Deuterostomia.

Amino Acid Sequence↗
PubMed2006

Hypoxia induces a complex response of globin expression in zebrafish (Danio rerio).

Unlike most mammals, many fish species live and survive in environments with low or changing levels of oxygen. Respiratory proteins like hemoglobin or myoglobin bind or store oxygen, thus enhancing its availability to the respiratory chain in the mitochondria. Here we investigate by means of quantitative real-time PCR the changes of hemoglobin, myoglobin, neuroglobin, cytoglobin and globin X mRNA in zebrafish (Danio rerio) exposed to mild (PO2=approximately 8.6 kPa) or severe (PO2=approximately 4.1 kPa) hypoxia. Neuroglobin and myoglobin protein levels were investigated by western blotting. Whereas mild hypoxia caused only minor changes of mRNA levels, strong hypoxia enhanced mRNA levels of the control genes (lactate dehydrogenase A and phosphoglycerate kinase 1). Surprisingly, levels of hemoglobin alpha and beta mRNA were significantly reduced under severe hypoxia. Myoglobin mRNA and protein in heart mildly increased, in line with its proposed oxygen supply function. Likewise, neuroglobin mRNA and protein significantly increased in brain (up to 5.7-fold at the protein level), but not in eye. This observation, firstly, suggests physiological differences of zebrafish eye and brain under hypoxia, and secondly, indicates an important role of neuroglobin in oxidative metabolism, probably oxygen supply within neurons. There was little change in the expression of the two cytoglobin genes. Globin X mRNA significantly decreased under hypoxia, pointing to a functional linkage to oxygen-dependent metabolism.

Animals↗