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Chronic hyperammonemia induces tonic activation of NMDA receptors in cerebellum.
- Source :
-
Journal of neurochemistry [J Neurochem] 2010 Feb; Vol. 112 (4), pp. 1005-14. Date of Electronic Publication: 2009 Nov 30. - Publication Year :
- 2010
-
Abstract
- Reduced function of the glutamate--nitric oxide (NO)--cGMP pathway is responsible for some cognitive alterations in rats with hyperammonemia and hepatic encephalopathy. Hyperammonemia impairs the pathway in cerebellum by increasing neuronal nitric oxide synthase (nNOS) phosphorylation in Ser847 by calcium-calmodulin-dependent protein kinase II (CaMKII), reducing nNOS activity, and by reducing nNOS amount in synaptic membranes, which reduces its activation following NMDA receptors activation. The reason for increased CaMKII activity in hyperammonemia remains unknown. We hypothesized that it would be as a result of increased tonic activation of NMDA receptors. The aims of this work were to assess: (i) whether tonic NMDA activation receptors is increased in cerebellum in chronic hyperammonemia in vivo; and (ii) whether this tonic activation is responsible for increased CaMKII activity and reduced activity of nNOS and of the glutamate--NO--cGMP pathway. Blocking NMDA receptors with MK-801 increases cGMP and NO metabolites in cerebellum in vivo and in slices from hyperammonemic rats. This is because of reduced phosphorylation and activity of CaMKII, leading to normalization of nNOS phosphorylation and activity. MK-801 also increases nNOS in synaptic membranes and reduces it in cytosol. This indicates that hyperammonemia increases tonic activation of NMDA receptors leading to reduced activity of nNOS and of the glutamate--NO--cGMP pathway.
- Subjects :
- Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism
Cerebellum drug effects
Cyclic GMP metabolism
Disease Models, Animal
Dizocilpine Maleate pharmacology
Excitatory Amino Acid Antagonists pharmacology
Glutamic Acid metabolism
In Vitro Techniques
Male
Microdialysis methods
Nitrates metabolism
Nitric Oxide Synthase Type I metabolism
Nitrites metabolism
Phosphorylation physiology
Rats
Rats, Wistar
Serine metabolism
Statistics, Nonparametric
Subcellular Fractions enzymology
Threonine metabolism
Cerebellum metabolism
Hyperammonemia pathology
Receptors, N-Methyl-D-Aspartate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1471-4159
- Volume :
- 112
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20002515
- Full Text :
- https://doi.org/10.1111/j.1471-4159.2009.06520.x