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Protein kinase C activity regulates D-serine availability in the brain
Charles Vargas-Lopes1, Caroline Madeira, Suzana A Kahn
1Laboratório de Fronteiras em Neurociências, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Journal of Neurochemistry
|November 13, 2010
Summary
Protein kinase C (PKC) phosphorylates serine racemase (SR), reducing D-serine levels crucial for NMDA receptor (NMDAR) function. This finding reveals a novel regulatory pathway for D-serine availability in the brain.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- D-serine acts as a co-agonist for NMDA receptors (NMDARs), playing a vital role in synaptic plasticity.
- Serine racemase (SR) is the primary enzyme responsible for synthesizing D-serine in the brain.
- SR interacts with protein interacting with C-kinase 1 (PICK1), a known regulator of protein kinase C (PKC) activity.
Purpose of the Study:
- To investigate the regulatory role of PKC activity on SR function and D-serine levels.
- To determine if PKC-mediated phosphorylation of SR impacts D-serine availability in neural systems.
Main Methods:
- In vitro experiments assessing the effect of PKC on SR activity and phosphorylation.
- Cell culture studies (astrocytes and neurons) to measure D-serine levels following PKC modulation.
- In vivo studies in rats to examine SR phosphorylation and D-serine levels in the frontal cortex.
- Behavioral testing (object recognition task) correlated with biochemical analyses in cortex and hippocampus.
Main Results:
- PKC activation led to increased SR phosphorylation and reduced D-serine levels in vitro and in cell cultures.
- PKC inhibition decreased SR phosphorylation and elevated D-serine levels.
- In vivo, PKC activity modulation directly affected SR phosphorylation and D-serine levels in rat brains.
- Rats performing an object recognition task exhibited decreased SR phosphorylation and increased D-serine/total serine ratios, linked to reduced PKC activity.
Conclusions:
- PKC directly phosphorylates SR at serine residues, thereby regulating D-serine availability in the brain.
- This PKC-SR interaction represents a significant mechanism for controlling D-serine levels.
- The findings suggest a potential link between PKC activity, SR phosphorylation, and NMDAR-dependent physiological and pathological processes.
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