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A review on hemeoxygenase-2: focus on cellular protection and oxygen response.

Muñoz-Sánchez J, Chánez-Cárdenas ME - Oxid Med Cell Longev (2014)

Bottom Line: Nevertheless, its abundance in tissues such as testis, endothelial cells, and particularly in brain, has pointed the relevance of HO-2 function.HO-2 presents particular characteristics that made it a unique protein in the HO system.Since attractive results on HO-2 have been arisen in later years, we focused this review in the second isoform.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, 14269 Delegación Tlalpan, DF, Mexico.

ABSTRACT
Hemeoxygenase (HO) system is responsible for cellular heme degradation to biliverdin, iron, and carbon monoxide. Two isoforms have been reported to date. Homologous HO-1 and HO-2 are microsomal proteins with more than 45% residue identity, share a similar fold and catalyze the same reaction. However, important differences between isoforms also exist. HO-1 isoform has been extensively studied mainly by its ability to respond to cellular stresses such as hemin, nitric oxide donors, oxidative damage, hypoxia, hyperthermia, and heavy metals, between others. On the contrary, due to its apparently constitutive nature, HO-2 has been less studied. Nevertheless, its abundance in tissues such as testis, endothelial cells, and particularly in brain, has pointed the relevance of HO-2 function. HO-2 presents particular characteristics that made it a unique protein in the HO system. Since attractive results on HO-2 have been arisen in later years, we focused this review in the second isoform. We summarize information on gene description, protein structure, and catalytic activity of HO-2 and particular facts such as its cellular impact and activity regulation. Finally, we call attention on the role of HO-2 in oxygen sensing, discussing proposed hypothesis on heme binding motifs and redox/thiol switches that participate in oxygen sensing as well as evidences of HO-2 response to hypoxia.

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Schematic representation of (a) enzimatic activity regulation; (b) redox regulation of HO-2 and BKCa channel. (a) Posttranslational modifications of HO-2 such as Ser 79 phosphorylation via PKC/CK2 can be activated by Glutamate/Ca2+, increasing HO-2 enzimatic activity. CaM/Ca2+ complex also can increase HO-2 activity through interaction between CaM and HO-2 due to an increase of Ca2+ by Glutamate. PTK may increase the activity of HO-2. (b) HO-2 and BKCa constitute a universal oxygen sensor system. Normoxic conditions: BKCa channel opens because inhibitor heme has dissociated from the channel or because CO generated by HO-2 is bound. In hypoxic conditions, CO levels are low and heme is bound to channel, hence BKCa is closed. Thus, heme is bound to HO-2 under normoxic conditions and to the HBD of the BKCa channel under hypoxia. Based on hypothesis proposed by Yi and Ragsdale 2007 [69] Williams et al. 2004 [70]; see text for details. BKCa channel: voltage- and Ca2+-activated large conductance K+ channel; CaM: calmodulin; CK2: Casein Kinase 2; PKC: Protein Kinase C; and PTK: Protein Tyrosine Kinase.
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Related In: Results  -  Collection


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fig5: Schematic representation of (a) enzimatic activity regulation; (b) redox regulation of HO-2 and BKCa channel. (a) Posttranslational modifications of HO-2 such as Ser 79 phosphorylation via PKC/CK2 can be activated by Glutamate/Ca2+, increasing HO-2 enzimatic activity. CaM/Ca2+ complex also can increase HO-2 activity through interaction between CaM and HO-2 due to an increase of Ca2+ by Glutamate. PTK may increase the activity of HO-2. (b) HO-2 and BKCa constitute a universal oxygen sensor system. Normoxic conditions: BKCa channel opens because inhibitor heme has dissociated from the channel or because CO generated by HO-2 is bound. In hypoxic conditions, CO levels are low and heme is bound to channel, hence BKCa is closed. Thus, heme is bound to HO-2 under normoxic conditions and to the HBD of the BKCa channel under hypoxia. Based on hypothesis proposed by Yi and Ragsdale 2007 [69] Williams et al. 2004 [70]; see text for details. BKCa channel: voltage- and Ca2+-activated large conductance K+ channel; CaM: calmodulin; CK2: Casein Kinase 2; PKC: Protein Kinase C; and PTK: Protein Tyrosine Kinase.

Mentions: It has been established that HO-2 activity is substrate dependent and that factors that increase heme substrate availability also increase CO production [96]. HO-2 activity can be affected by posttranslational modifications. In vitro studies have shown that HO-2 activity is influenced by CK2-dependent phosphorylation at Ser 79 and that PKC protein could be implicated in this mechanism. In hippocampal culture, activation of PKC via phorbol ester treatment directly phosphorylates and activates CK-2, which in turn phosphorylates and activates HO-2 [97]. Authors suggested that HO-2 activation via PKC during neuronal depolarization could also involve Ca2+ entry. Later they demonstrated that Ca2+ mobilizing agents, such as ionomycin and glutamate, stimulate endogenous HO-2 activity in primary cortical culture. Results using a calmodulin mutant Phe 66 (a key amino acid in the calmodulin binding motif) showed that this Ca2+/calmodulin activation depends on the interaction between calmodulin and HO-2 and that this phenomenon is independent of CK2 activation. Apparently conformational changes in HO-2 induced by calmodulin binding are responsible for HO-2 activation. A similar conformational change in HO-2 could be occurring by phosphorylation of Ser 79 even both HO-2 activation mechanisms are independent and not additive [98]. The HO-2 activation by Ca2+/calmodulin-dependent mechanisms by glutamate has been also observed in piglet astrocytes [99]. Although actually it is not completely clear, it has been suggested that tyrosine phosphorylation stimulates HO-2 catalytic activity. Results showed that a PTK inhibitor reduces the HO-2 catalytic activity in cerebral microvessels, while the inhibition of protein tyrosine phosphatases increases it [100] (Figure 5(a)).


A review on hemeoxygenase-2: focus on cellular protection and oxygen response.

Muñoz-Sánchez J, Chánez-Cárdenas ME - Oxid Med Cell Longev (2014)

Schematic representation of (a) enzimatic activity regulation; (b) redox regulation of HO-2 and BKCa channel. (a) Posttranslational modifications of HO-2 such as Ser 79 phosphorylation via PKC/CK2 can be activated by Glutamate/Ca2+, increasing HO-2 enzimatic activity. CaM/Ca2+ complex also can increase HO-2 activity through interaction between CaM and HO-2 due to an increase of Ca2+ by Glutamate. PTK may increase the activity of HO-2. (b) HO-2 and BKCa constitute a universal oxygen sensor system. Normoxic conditions: BKCa channel opens because inhibitor heme has dissociated from the channel or because CO generated by HO-2 is bound. In hypoxic conditions, CO levels are low and heme is bound to channel, hence BKCa is closed. Thus, heme is bound to HO-2 under normoxic conditions and to the HBD of the BKCa channel under hypoxia. Based on hypothesis proposed by Yi and Ragsdale 2007 [69] Williams et al. 2004 [70]; see text for details. BKCa channel: voltage- and Ca2+-activated large conductance K+ channel; CaM: calmodulin; CK2: Casein Kinase 2; PKC: Protein Kinase C; and PTK: Protein Tyrosine Kinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4127239&req=5

fig5: Schematic representation of (a) enzimatic activity regulation; (b) redox regulation of HO-2 and BKCa channel. (a) Posttranslational modifications of HO-2 such as Ser 79 phosphorylation via PKC/CK2 can be activated by Glutamate/Ca2+, increasing HO-2 enzimatic activity. CaM/Ca2+ complex also can increase HO-2 activity through interaction between CaM and HO-2 due to an increase of Ca2+ by Glutamate. PTK may increase the activity of HO-2. (b) HO-2 and BKCa constitute a universal oxygen sensor system. Normoxic conditions: BKCa channel opens because inhibitor heme has dissociated from the channel or because CO generated by HO-2 is bound. In hypoxic conditions, CO levels are low and heme is bound to channel, hence BKCa is closed. Thus, heme is bound to HO-2 under normoxic conditions and to the HBD of the BKCa channel under hypoxia. Based on hypothesis proposed by Yi and Ragsdale 2007 [69] Williams et al. 2004 [70]; see text for details. BKCa channel: voltage- and Ca2+-activated large conductance K+ channel; CaM: calmodulin; CK2: Casein Kinase 2; PKC: Protein Kinase C; and PTK: Protein Tyrosine Kinase.
Mentions: It has been established that HO-2 activity is substrate dependent and that factors that increase heme substrate availability also increase CO production [96]. HO-2 activity can be affected by posttranslational modifications. In vitro studies have shown that HO-2 activity is influenced by CK2-dependent phosphorylation at Ser 79 and that PKC protein could be implicated in this mechanism. In hippocampal culture, activation of PKC via phorbol ester treatment directly phosphorylates and activates CK-2, which in turn phosphorylates and activates HO-2 [97]. Authors suggested that HO-2 activation via PKC during neuronal depolarization could also involve Ca2+ entry. Later they demonstrated that Ca2+ mobilizing agents, such as ionomycin and glutamate, stimulate endogenous HO-2 activity in primary cortical culture. Results using a calmodulin mutant Phe 66 (a key amino acid in the calmodulin binding motif) showed that this Ca2+/calmodulin activation depends on the interaction between calmodulin and HO-2 and that this phenomenon is independent of CK2 activation. Apparently conformational changes in HO-2 induced by calmodulin binding are responsible for HO-2 activation. A similar conformational change in HO-2 could be occurring by phosphorylation of Ser 79 even both HO-2 activation mechanisms are independent and not additive [98]. The HO-2 activation by Ca2+/calmodulin-dependent mechanisms by glutamate has been also observed in piglet astrocytes [99]. Although actually it is not completely clear, it has been suggested that tyrosine phosphorylation stimulates HO-2 catalytic activity. Results showed that a PTK inhibitor reduces the HO-2 catalytic activity in cerebral microvessels, while the inhibition of protein tyrosine phosphatases increases it [100] (Figure 5(a)).

Bottom Line: Nevertheless, its abundance in tissues such as testis, endothelial cells, and particularly in brain, has pointed the relevance of HO-2 function.HO-2 presents particular characteristics that made it a unique protein in the HO system.Since attractive results on HO-2 have been arisen in later years, we focused this review in the second isoform.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, 14269 Delegación Tlalpan, DF, Mexico.

ABSTRACT
Hemeoxygenase (HO) system is responsible for cellular heme degradation to biliverdin, iron, and carbon monoxide. Two isoforms have been reported to date. Homologous HO-1 and HO-2 are microsomal proteins with more than 45% residue identity, share a similar fold and catalyze the same reaction. However, important differences between isoforms also exist. HO-1 isoform has been extensively studied mainly by its ability to respond to cellular stresses such as hemin, nitric oxide donors, oxidative damage, hypoxia, hyperthermia, and heavy metals, between others. On the contrary, due to its apparently constitutive nature, HO-2 has been less studied. Nevertheless, its abundance in tissues such as testis, endothelial cells, and particularly in brain, has pointed the relevance of HO-2 function. HO-2 presents particular characteristics that made it a unique protein in the HO system. Since attractive results on HO-2 have been arisen in later years, we focused this review in the second isoform. We summarize information on gene description, protein structure, and catalytic activity of HO-2 and particular facts such as its cellular impact and activity regulation. Finally, we call attention on the role of HO-2 in oxygen sensing, discussing proposed hypothesis on heme binding motifs and redox/thiol switches that participate in oxygen sensing as well as evidences of HO-2 response to hypoxia.

Show MeSH
Related in: MedlinePlus