Journal
JOURNAL OF NEUROCHEMISTRY
Volume 116, Issue 2, Pages 281-290Publisher
WILEY
DOI: 10.1111/j.1471-4159.2010.07102.x
Keywords
brain; d-serine; NMDAR function; phosphorylation; protein kinase C; serine racemase
Categories
Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
- Fundacao Universitaria Jose Bonifacio (FUJB)
- Instituto Nacional de Neurociencia Translacional (INNP)
- International Society for Neurochemistry
- Human Frontier Science Program (HFSP)
- CAPES
- ICB, UFRJ
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P>d-Serine is a co-agonist of NMDA receptor (NMDAR) and plays important roles in synaptic plasticity mechanisms. Serine racemase (SR) is a brain-enriched enzyme that converts l-serine to d-serine. SR interacts with the protein interacting with C-kinase 1 (PICK1), which is known to direct protein kinase C (PKC) to its targets in cells. Here, we investigated whether PKC activity regulates SR activity and d-serine availability in the brain. In vitro, PKC phosphorylated SR and decreased its activity. PKC activation increased SR phosphorylation in serine residues and reduced d-serine levels in astrocyte and neuronal cultures. Conversely, PKC inhibition decreased basal SR phosphorylation and increased cellular d-serine levels. In vivo modulation of PKC activity regulated both SR phosphorylation and d-serine levels in rat frontal cortex. Finally, rats that completed an object recognition task showed decreased SR phosphorylation and increased d-serine/total serine ratios, which was markedly correlated with decreased PKC activity in both cortex and hippocampus. Results indicate that PKC phosphorylates SR in serine residues and regulates d-serine availability in the brain. This interaction may be relevant for the regulation of physiological and pathological mechanisms linked to NMDAR function.
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