Chronic hyperammonemia induces tonic activation of NMDA receptors in cerebellum.
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.
ElMlili
Nisrin
N
Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Valencia, Spain.
Boix
Jordi
J
Ahabrach
Hanan
H
Rodrigo
Regina
R
Errami
Mohammed
M
Felipo
Vicente
V
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D022124:Hyperammonemia / Q000473:pathology*; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis / Q000379:methods; D009566:Nitrates / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D018709:Statistics, Nonparametric; D013347:Subcellular Fractions / Q000201:enzymology; D013912:Threonine / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D009566:Nitrates; D009573:Nitrites; D016194:Receptors, N-Methyl-D-Aspartate; D013912:Threonine; D018698:Glutamic Acid; D012694:Serine; D016291:Dizocilpine Maleate; D052248:Nitric Oxide Synthase Type I; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006152:Cyclic GMP