Limits...
Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration.

Santos RM, Lourenço CF, Ledo A, Barbosa RM, Laranjinha J - Int J Cell Biol (2012)

Bottom Line: The ambient (•)NO concentration reflects the balance between the rate of synthesis and the rate of breakdown.Much has been learnt about the mechanism of (•)NO synthesis, but the inactivation pathways of (•)NO has been almost completely ignored.We have recently addressed these issues in vivo on basis of microelectrode technology that allows a fine-tuned spatial and temporal measurement (•)NO concentration dynamics in the brain.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmacy and Center for Neurosciences and Cell Biology, University of Coimbra, Health Sciences Campus, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.

ABSTRACT
During the last decades nitric oxide ((•)NO) has emerged as a critical physiological signaling molecule in mammalian tissues, notably in the brain. (•)NO may modify the activity of regulatory proteins via direct reaction with the heme moiety, or indirectly, via S-nitrosylation of thiol groups or nitration of tyrosine residues. However, a conceptual understanding of how (•)NO bioactivity is carried out in biological systems is hampered by the lack of knowledge on its dynamics in vivo. Key questions still lacking concrete and definitive answers include those related with quantitative issues of its concentration dynamics and diffusion, summarized in the how much, how long, and how far trilogy. For instance, a major problem is the lack of knowledge of what constitutes a physiological (•)NO concentration and what constitutes a pathological one and how is (•)NO concentration regulated. The ambient (•)NO concentration reflects the balance between the rate of synthesis and the rate of breakdown. Much has been learnt about the mechanism of (•)NO synthesis, but the inactivation pathways of (•)NO has been almost completely ignored. We have recently addressed these issues in vivo on basis of microelectrode technology that allows a fine-tuned spatial and temporal measurement (•)NO concentration dynamics in the brain.

No MeSH data available.


Related in: MedlinePlus

The major pathways of •NO production and inactivation in the brain. (a) •NO is synthesized following calcium entrance into the postsynaptic density (upon glutamate activation of NMDA receptors). Calcium activates nNOS by promoting Calmodulin (CaM) binding to the enzyme. •NO rapidly diffuses to neighboring tissue, being inactivated both by O2-dependent mechanisms and by scavenging by circulating erythrocytes (RBCs). (b) Typical electrochemical signals obtained using microelectrodes in the rat brain in vivo and in agarose gel following local application of small volumes (few nL) of •NO solution. First-order decay constant values (k) were used to quantify the decay profiles. (c) Anoxia, induced by a nitrite lethal dose, induced a 20% decrease in k (k2), in contrast with a large decrease in k following cardiac arrest, suggesting that the major route of •NO inactivation in the brain in vivo is by circulating RBCs scavenging (k1). Adapted from [10].
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3376480&req=5

fig1: The major pathways of •NO production and inactivation in the brain. (a) •NO is synthesized following calcium entrance into the postsynaptic density (upon glutamate activation of NMDA receptors). Calcium activates nNOS by promoting Calmodulin (CaM) binding to the enzyme. •NO rapidly diffuses to neighboring tissue, being inactivated both by O2-dependent mechanisms and by scavenging by circulating erythrocytes (RBCs). (b) Typical electrochemical signals obtained using microelectrodes in the rat brain in vivo and in agarose gel following local application of small volumes (few nL) of •NO solution. First-order decay constant values (k) were used to quantify the decay profiles. (c) Anoxia, induced by a nitrite lethal dose, induced a 20% decrease in k (k2), in contrast with a large decrease in k following cardiac arrest, suggesting that the major route of •NO inactivation in the brain in vivo is by circulating RBCs scavenging (k1). Adapted from [10].

Mentions: A strategy to the study of the mechanisms that govern •NO inactivation in vivo has included the recordings of •NO signals by •NO-selective microelectrodes, following local application of small volumes of exogenous •NO in the brain [10]. The decay of •NO signals obtained by means of this approach was very sensitive to experimental conditions impairing vascular function in vivo. First, global ischemia induced a 90% decrease in the •NO signals decay rate constant (k), suggesting that •NO inactivation is nearly abolished during this condition. Second, the k values of •NO signals decay were 3–5-fold higher in vivo than in brain slices of cortex and hippocampus, which lack functional vasculature. Finally, impairing the microcirculation in the brain in vivo by inducing hemorrhagic shock induced an average 50% decrease in k. Comparatively, modulation of O2 tension in the brain in vivo, either by inducing hypoxia or hyperoxia, caused only small changes in •NO decay (20%), thus demonstrating that scavenging by circulating red blood cells constitutes the major •NO inactivation pathway in the brain (Figure 1).


Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration.

Santos RM, Lourenço CF, Ledo A, Barbosa RM, Laranjinha J - Int J Cell Biol (2012)

The major pathways of •NO production and inactivation in the brain. (a) •NO is synthesized following calcium entrance into the postsynaptic density (upon glutamate activation of NMDA receptors). Calcium activates nNOS by promoting Calmodulin (CaM) binding to the enzyme. •NO rapidly diffuses to neighboring tissue, being inactivated both by O2-dependent mechanisms and by scavenging by circulating erythrocytes (RBCs). (b) Typical electrochemical signals obtained using microelectrodes in the rat brain in vivo and in agarose gel following local application of small volumes (few nL) of •NO solution. First-order decay constant values (k) were used to quantify the decay profiles. (c) Anoxia, induced by a nitrite lethal dose, induced a 20% decrease in k (k2), in contrast with a large decrease in k following cardiac arrest, suggesting that the major route of •NO inactivation in the brain in vivo is by circulating RBCs scavenging (k1). Adapted from [10].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376480&req=5

fig1: The major pathways of •NO production and inactivation in the brain. (a) •NO is synthesized following calcium entrance into the postsynaptic density (upon glutamate activation of NMDA receptors). Calcium activates nNOS by promoting Calmodulin (CaM) binding to the enzyme. •NO rapidly diffuses to neighboring tissue, being inactivated both by O2-dependent mechanisms and by scavenging by circulating erythrocytes (RBCs). (b) Typical electrochemical signals obtained using microelectrodes in the rat brain in vivo and in agarose gel following local application of small volumes (few nL) of •NO solution. First-order decay constant values (k) were used to quantify the decay profiles. (c) Anoxia, induced by a nitrite lethal dose, induced a 20% decrease in k (k2), in contrast with a large decrease in k following cardiac arrest, suggesting that the major route of •NO inactivation in the brain in vivo is by circulating RBCs scavenging (k1). Adapted from [10].
Mentions: A strategy to the study of the mechanisms that govern •NO inactivation in vivo has included the recordings of •NO signals by •NO-selective microelectrodes, following local application of small volumes of exogenous •NO in the brain [10]. The decay of •NO signals obtained by means of this approach was very sensitive to experimental conditions impairing vascular function in vivo. First, global ischemia induced a 90% decrease in the •NO signals decay rate constant (k), suggesting that •NO inactivation is nearly abolished during this condition. Second, the k values of •NO signals decay were 3–5-fold higher in vivo than in brain slices of cortex and hippocampus, which lack functional vasculature. Finally, impairing the microcirculation in the brain in vivo by inducing hemorrhagic shock induced an average 50% decrease in k. Comparatively, modulation of O2 tension in the brain in vivo, either by inducing hypoxia or hyperoxia, caused only small changes in •NO decay (20%), thus demonstrating that scavenging by circulating red blood cells constitutes the major •NO inactivation pathway in the brain (Figure 1).

Bottom Line: The ambient (•)NO concentration reflects the balance between the rate of synthesis and the rate of breakdown.Much has been learnt about the mechanism of (•)NO synthesis, but the inactivation pathways of (•)NO has been almost completely ignored.We have recently addressed these issues in vivo on basis of microelectrode technology that allows a fine-tuned spatial and temporal measurement (•)NO concentration dynamics in the brain.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmacy and Center for Neurosciences and Cell Biology, University of Coimbra, Health Sciences Campus, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.

ABSTRACT
During the last decades nitric oxide ((•)NO) has emerged as a critical physiological signaling molecule in mammalian tissues, notably in the brain. (•)NO may modify the activity of regulatory proteins via direct reaction with the heme moiety, or indirectly, via S-nitrosylation of thiol groups or nitration of tyrosine residues. However, a conceptual understanding of how (•)NO bioactivity is carried out in biological systems is hampered by the lack of knowledge on its dynamics in vivo. Key questions still lacking concrete and definitive answers include those related with quantitative issues of its concentration dynamics and diffusion, summarized in the how much, how long, and how far trilogy. For instance, a major problem is the lack of knowledge of what constitutes a physiological (•)NO concentration and what constitutes a pathological one and how is (•)NO concentration regulated. The ambient (•)NO concentration reflects the balance between the rate of synthesis and the rate of breakdown. Much has been learnt about the mechanism of (•)NO synthesis, but the inactivation pathways of (•)NO has been almost completely ignored. We have recently addressed these issues in vivo on basis of microelectrode technology that allows a fine-tuned spatial and temporal measurement (•)NO concentration dynamics in the brain.

No MeSH data available.


Related in: MedlinePlus