Protein F1 and protein kinase C may regulate the persistence, not the initiation, of synaptic potentiation in the hippocampus.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
D M Lovinger
Publications and source records attributed to D M Lovinger.
Direct relation of long-term synaptic potentiation to phosphorylation of membrane protein F1, a substrate for membrane protein kinase C.
One hour after long-term potentiation (LTP) in the intact hippocampus, a selective increase in protein F1 in vitro phosphorylation was observed in homogenate prepared from dorsal hippocampus. Protein F1 phosphorylation was directly related to the magnitude and persistence of potentiation. No other phosphoprotein studied exhibited a relationship with synaptic enhancement. Low-frequency, non-potentiating stimulation did not increase protein F1 phosphorylation, and phosphorylation of F1 was not elevated when high-frequency stimulation did not produce potentiation. We also confirmed our earlier demonstration of a similar pattern of results 5 min after LTP. In related work we have previously observed: that protein F1 is a substrate for protein kinase C (PKC); that membrane PKC activity was increased by translocation from the cytosol following LTP; and that membrane PKC activity was directly related to the persistence of enhancement. We therefore predicted in the present study that protein F1 phosphorylation in a dorsal hippocampal membrane fraction would be related to LTP. Hippocampal membrane protein F1 was found to be directly related to both the magnitude and persistence of response enhancement. Thus the molecular events leading to prolonged potentiation may involve increased PKC/protein F1 association. Persistence of potentiation may be related to synaptic growth processes involving the growth-associated function of protein F1.
Animals↗
Translocation of protein kinase C activity may mediate hippocampal long-term potentiation.
Protein kinase C activity in rat hippocampal membranes and cytosol was determined 1 minute and 1 hour after induction of the synaptic plasticity of long-term potentiation. At 1 hour after long-term potentiation, but not at 1 minute, protein kinase C activity was increased twofold in membranes and decreased proportionately in cytosol, suggesting translocation of the activity. This time-dependent redistribution of enzyme activity was directly related to the persistence of synaptic plasticity, suggesting a novel mechanism regulating the strength of synaptic transmission.
Animals↗
A selective increase in phosporylation of protein F1, a protein kinase C substrate, directly related to three day growth of long term synaptic enhancement.
Increased in vitro phosphorylation of the 47 kdalton, 4.5 pI protein F1 was observed in dorsal hippocampal tissue from animals exhibiting long term enhancement (LTE) three days after high frequency stimulation of the perforant pathway, as compared to tissue from low frequency stimulated controls or from unoperated animals. The increase in protein F1 phosphorylation was related to LTE rather than simple activation of perforant path-dentate gyrus synapses. This is the first report of a change in brain protein phosphorylation accompanying synaptic enhancement lasting days. The extent of growth of LTE over the three days following stimulation was directly related (r = +0.66, P less than 0.05) to protein F1 phosphorylation. Among the phosphoproteins studied this relationship between LTE and phosphorylation was selective for protein F1. This suggests that protein F1 may regulate growth of synaptic plasticity for at least a three day period. The mechanism for the LTE-related increase in protein F1 phosphorylation has not been established. However, recent evidence from this laboratory indicates: that protein F1 is phosphorylated by the calcium/phospholipid-dependent protein kinase C; and that kinase C is activated 1 h after LTE. Therefore, the increase in protein F1 phosphorylation following LTE may result from long term activation of protein C kinase.
Animals↗
Selective increase in phosphorylation of a 47-kDa protein (F1) directly related to long-term potentiation.
Five minutes after the induction of long-term potentiation (LTP) in the intact hippocampal formation of chloralose/urethane-anesthetized rats there was a selective increase in the in vitro phosphorylation state of a 47-kDa band (designated Protein F1). When low frequency, nonpotentiating stimulation was used, no change in Protein F1 was observed. LTP had no significant effect on other phosphoproteins measured at the 5-min time point. In vitro phosphorylation of Protein F1 5 min after LTP was directly related to the change in synaptic efficiency (r = +0.86, p less than .01). The calcium-dependent, synaptically localized Protein F1 may be the same as the brain-specific Protein B-50. The regulation of the plastic LTP response may involve the novel multifunctional phospholipid-dependent enzyme, Protein Kinase C, which has been shown to phosphorylate B50.
Animals↗
Selective decline in protein F1 phosphorylation in hippocampus of senescent rats.
Certain forms of neuronal plasticity have been found to be expressed through alterations in brain protein phosphorylation, and its regulation by protein kinase activity. Of interest in this regard is the possibility that the decline in neuronal plasticity and cognitive function that occurs in advanced age may result in part from altered phosphorylation of specific proteins. As a first attempt to identify age-related changes in phosphoproteins, we assayed in vitro phosphorylation of proteins in hippocampus, cerebellum, entorhinal cortex, and frontal cortex from Fischer-344 rats of 5 months, 11 months, and 25 months of age. Compared to the middle-aged animals, the aged rats showed a selective 46% decline in phosphorylation of the 47 kDa protein (F1) in hippocampus, with no change in the phosphorylation of other proteins measured in this structure. Aged animals also showed decreased phosphorylation relative to young animals. No age-related change was observed in any protein band for the other brain areas examined. Since protein F1 is phosphorylated by protein kinase C (PKC), the cytosolic and membrane distribution of this enzyme was compared across age groups. The activity of PKC in hippocampus did not change across age. The explanation of this age-related decline in protein F1 phosphorylation is likely to be a decline in the substrate protein itself. The results are discussed in terms of protein F1's possible role in age-related decline of hippocampal synaptic plasticity.
Aging↗