Resumo

D-serine is a co-agonist of N-methyl-D-aspartate receptor (NMDAR) and plays important roles in synaptic plasticity. 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 regulates SR activity and D-serine availability in the brain. SR presents conserved consensus sequences for PKC phosphorylation across rodents and humans. In vitro, PKC phosphorylated SR and decreased its activity by 50%. SR, PKC and PICK1 co-localized and co-immunoprecipitated in both astrocytes and neurons. PKC activation increased SR phosphorylation and reduced in 40% the levels of D-serine in astrocyte and neuronal cultures. Conversely, PKC inhibition decreased basal SR phosphorylation and increased cellular D-serine levels by 30%. SR, PKC and PICK1 co-immunoprecipitated from rat brain and in vivo modulation of PKC activity regulated significantly 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 levels in both cortex and hippocampus by 30%. Results indicate that PKC phosphorylates SR and regulates D-serine availability in the brain. This interaction may be relevant for regulation of physiological and pathological mechanisms linked to NMDAR function.