Protein phosphatase-mediated regulation of protein kinase C during long-term depression in the adult hippocampus in vivo.
The neural substrates of learning and memory are thought to involve use-dependent long-term changes in synaptic function, including long-term depression (LTD) of synaptic strength. One biochemical event hypothesized to contribute to the maintenance and expression of LTD is decreased protein phosphorylation, caused by a decrease in protein kinase activity and/or an increase in protein phosphatase activity. We tested whether the activity of protein kinase C (PKC) decreases after the induction of LTD in area CA1 of the adult hippocampus in vivo, and then investigated the mechanism responsible for the LTD-associated alteration in PKC activity. We found that LTD was associated with a significant decrease in both autonomous and cofactor-dependent PKC activity. The decrease in PKC activity was prevented by NMDA receptor blockade and was not accompanied by a decrease in the level of either PKCalpha, beta, gamma, or zeta. Western blot analysis with phosphospecific antibodies revealed that phosphorylation of Ser-657 on the catalytic domain of PKCalpha (Ser-660 on PKCbetaII) was decreased significantly after the induction of LTD, and that this dephosphorylation was prevented by the protein phosphatase inhibitor okadaic acid. The decrease in autonomous and cofactor-dependent PKC activity likewise was prevented by okadaic acid. These findings suggest that LTD in the adult hippocampus in vivo involves a decrease in PKC activity that is mediated, at least in part, by dephosphorylation of the catalytic domain of PKC by protein phosphatases activated after LTD-inducing stimulation. Our findings are consistent with the idea that protein dephosphorylation contributes to the expression of LTD.
Thiels
E
E
Department of Neuroscience and Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. thiels@bns.pitt.edu
Kanterewicz
B I
BI
Knapp
L T
LT
Barrionuevo
G
G
Klann
E
E
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D020134:Catalytic Domain / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000201:enzymology* / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D007858:Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology*; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D009435:Synaptic Transmission / Q000502:physiology; D013995:Time
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010761:Phosphorus Radioisotopes; D016194:Receptors, N-Methyl-D-Aspartate; D019319:Okadaic Acid; D015763:2-Amino-5-phosphonovalerate; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases