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Extracellular Protein Kinase A Modulates Intracellular Calcium/Calmodulin-Dependent Protein Kinase II, Nitric Oxide Synthase, and the Glutamate-Nitric Oxide-cGMP Pathway in Cerebellum. Differential Effects in Hyperammonemia.
ACS Chem Neurosci. 2016 12 21; 7(12):1753-1759.AC

Abstract

Extracellular protein kinases, including cAMP-dependent protein kinase (PKA), modulate neuronal functions including N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation. NMDA receptor activation increases calcium, which binds to calmodulin and activates nitric oxide synthase (NOS), increasing nitric oxide (NO), which activates guanylate cyclase, increasing cGMP, which is released to the extracellular fluid, allowing analysis of this glutamate-NO-cGMP pathway in vivo by microdialysis. The function of this pathway is impaired in hyperammonemic rats. The aims of this work were to assess (1) whether the glutamate-NO-cGMP pathway is modulated in cerebellum in vivo by an extracellular PKA, (2) the role of phosphorylation and activity of calcium/calmodulin-dependent protein kinase II (CaMKII) and NOS in the pathway modulation by extracellular PKA, and (3) whether the effects are different in hyperammonemic and control rats. The pathway was analyzed by in vivo microdialysis. The role of extracellular PKA was analyzed by inhibiting it with a membrane-impermeable inhibitor. The mechanisms involved were analyzed in freshly isolated cerebellar slices from control and hyperammonemic rats. In control rats, inhibiting extracellular PKA reduces the glutamate-NO-cGMP pathway function in vivo. This is due to reduction of CaMKII phosphorylation and activity, which reduces NOS phosphorylation at Ser1417 and NOS activity, resulting in reduced guanylate cyclase activation and cGMP formation. In hyperammonemic rats, under basal conditions, CaMKII phosphorylation and activity are increased, increasing NOS phosphorylation at Ser847, which reduces NOS activity, guanylate cyclase activation, and cGMP. Inhibiting extracellular PKA in hyperammonemic rats normalizes CaMKII phosphorylation and activity, NOS phosphorylation, NOS activity, and cGMP, restoring normal function of the pathway.

Authors+Show Affiliations

Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe , Eduardo Primo-Yufera 3, 46012 Valencia, Spain.Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe , Eduardo Primo-Yufera 3, 46012 Valencia, Spain.Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe , Eduardo Primo-Yufera 3, 46012 Valencia, Spain.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27673574

Citation

Cabrera-Pastor, Andrea, et al. "Extracellular Protein Kinase a Modulates Intracellular Calcium/Calmodulin-Dependent Protein Kinase II, Nitric Oxide Synthase, and the Glutamate-Nitric Oxide-cGMP Pathway in Cerebellum. Differential Effects in Hyperammonemia." ACS Chemical Neuroscience, vol. 7, no. 12, 2016, pp. 1753-1759.
Cabrera-Pastor A, Llansola M, Felipo V. Extracellular Protein Kinase A Modulates Intracellular Calcium/Calmodulin-Dependent Protein Kinase II, Nitric Oxide Synthase, and the Glutamate-Nitric Oxide-cGMP Pathway in Cerebellum. Differential Effects in Hyperammonemia. ACS Chem Neurosci. 2016;7(12):1753-1759.
Cabrera-Pastor, A., Llansola, M., & Felipo, V. (2016). Extracellular Protein Kinase A Modulates Intracellular Calcium/Calmodulin-Dependent Protein Kinase II, Nitric Oxide Synthase, and the Glutamate-Nitric Oxide-cGMP Pathway in Cerebellum. Differential Effects in Hyperammonemia. ACS Chemical Neuroscience, 7(12), 1753-1759. https://doi.org/10.1021/acschemneuro.6b00263
Cabrera-Pastor A, Llansola M, Felipo V. Extracellular Protein Kinase a Modulates Intracellular Calcium/Calmodulin-Dependent Protein Kinase II, Nitric Oxide Synthase, and the Glutamate-Nitric Oxide-cGMP Pathway in Cerebellum. Differential Effects in Hyperammonemia. ACS Chem Neurosci. 2016 12 21;7(12):1753-1759. PubMed PMID: 27673574.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Extracellular Protein Kinase A Modulates Intracellular Calcium/Calmodulin-Dependent Protein Kinase II, Nitric Oxide Synthase, and the Glutamate-Nitric Oxide-cGMP Pathway in Cerebellum. Differential Effects in Hyperammonemia. AU - Cabrera-Pastor,Andrea, AU - Llansola,Marta, AU - Felipo,Vicente, Y1 - 2016/10/05/ PY - 2016/9/28/pubmed PY - 2017/10/21/medline PY - 2016/9/28/entrez KW - Extracellular protein kinase A KW - calcium/calmodulin-dependent protein kinase II KW - glutamate−NO−cGMP pathway KW - hyperammonemia KW - nitric oxide synthase KW - phosphorylation SP - 1753 EP - 1759 JF - ACS chemical neuroscience JO - ACS Chem Neurosci VL - 7 IS - 12 N2 - Extracellular protein kinases, including cAMP-dependent protein kinase (PKA), modulate neuronal functions including N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation. NMDA receptor activation increases calcium, which binds to calmodulin and activates nitric oxide synthase (NOS), increasing nitric oxide (NO), which activates guanylate cyclase, increasing cGMP, which is released to the extracellular fluid, allowing analysis of this glutamate-NO-cGMP pathway in vivo by microdialysis. The function of this pathway is impaired in hyperammonemic rats. The aims of this work were to assess (1) whether the glutamate-NO-cGMP pathway is modulated in cerebellum in vivo by an extracellular PKA, (2) the role of phosphorylation and activity of calcium/calmodulin-dependent protein kinase II (CaMKII) and NOS in the pathway modulation by extracellular PKA, and (3) whether the effects are different in hyperammonemic and control rats. The pathway was analyzed by in vivo microdialysis. The role of extracellular PKA was analyzed by inhibiting it with a membrane-impermeable inhibitor. The mechanisms involved were analyzed in freshly isolated cerebellar slices from control and hyperammonemic rats. In control rats, inhibiting extracellular PKA reduces the glutamate-NO-cGMP pathway function in vivo. This is due to reduction of CaMKII phosphorylation and activity, which reduces NOS phosphorylation at Ser1417 and NOS activity, resulting in reduced guanylate cyclase activation and cGMP formation. In hyperammonemic rats, under basal conditions, CaMKII phosphorylation and activity are increased, increasing NOS phosphorylation at Ser847, which reduces NOS activity, guanylate cyclase activation, and cGMP. Inhibiting extracellular PKA in hyperammonemic rats normalizes CaMKII phosphorylation and activity, NOS phosphorylation, NOS activity, and cGMP, restoring normal function of the pathway. SN - 1948-7193 UR - https://www.unboundmedicine.com/medline/citation/27673574/Extracellular_Protein_Kinase_A_Modulates_Intracellular_Calcium/Calmodulin_Dependent_Protein_Kinase_II_Nitric_Oxide_Synthase_and_the_Glutamate_Nitric_Oxide_cGMP_Pathway_in_Cerebellum__Differential_Effects_in_Hyperammonemia_ L2 - https://doi.org/10.1021/acschemneuro.6b00263 DB - PRIME DP - Unbound Medicine ER -