Protein kinase C activity regulates D-serine availability in the brain.
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.
Laboratório de Fronteiras em Neurociências, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Charles
C
Vargas-Lopes
Caroline
C
Madeira
Suzana A
SA
Kahn
Ingrid
I
Albino do Couto
Patricia
P
Bado
Jean Christophe
JC
Houzel
Joari
J
De Miranda
Marta S
MS
de Freitas
Sergio T
ST
Ferreira
Rogerio
R
Panizzutti
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D019998:Racemases and Epimerases / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D021641:Recognition, Psychology / Q000502:physiology; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D000099300:Serine Racemase
D011493:Protein Kinase C; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase