Translocation of Protein Kinase C Activity May Mediate Hippocampal Long-Term Potentiation

Akers, Raymond F.; Lovinger, David M.; Colley, Patricia A.; Linden, David J.; Routtenberg, Aryeh

doi:10.1126/science.3003904

Cited by 526 publications

(159 citation statements)

References 18 publications

Supporting

Mentioning

147

Contrasting

Order By: Relevance

“…These results support the interpretation that PKC trafficking is required for PKC-dependent Src activation and subsequent regulation of NMDA channel activity. This judgment receives support from previous in vitro biochemical investigations (44).…”

Section: Src Signaling Pathway Is Not Required For Pkc-inducedmentioning

confidence: 87%

Protein Kinase C Promotes N-Methyl-d-aspartate (NMDA) Receptor Trafficking by Indirectly Triggering Calcium/Calmodulin-dependent Protein Kinase II (CaMKII) Autophosphorylation

Yan

Ren

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Regulation of neuronal NMDA receptor (NMDAR) is critical in synaptic transmission and plasticity. Protein kinase C (PKC) promotes NMDAR trafficking to the cell surface via interaction with NMDAR-associated proteins (NAPs). Little is known, however, about the NAPs that are critical to PKC-induced NMDAR trafficking. Here, we showed that calcium/calmodulin-dependent protein kinase II (CaMKII) could be a NAP that mediates the potentiation of NMDAR trafficking by PKC. PKC activation promoted the level of autophosphorylated CaMKII and increased association with NMDARs, accompanied by functional NMDAR insertion, at postsynaptic sites. This potentiation, along with PKC-induced long term potentiation of the AMPA receptor-mediated response, was abolished by CaMKII antagonist or by disturbing the interaction between CaMKII and NR2A or NR2B. Further mutual occlusion experiments demonstrated that PKC and CaMKII share a common signaling pathway in the potentiation of NMDAR trafficking and longterm potentiation (LTP) induction. Our results revealed that PKC promotes NMDA receptor trafficking and induces synaptic plasticity through indirectly triggering CaMKII autophosphorylation and subsequent increased association with NMDARs.The NMDA receptor (NMDAR) 3 plays a critical role in neural development, learning and memory, sensory perception, and synaptic plasticity (1, 2). Therefore, regulation of neuronal NMDARs is of great importance to synaptic transmission. PKC increases the NMDA channel opening rate and delivers new NMDARs to the plasma membrane through regulated exocytosis (3, 4). This potentiation of NMDAR trafficking is not due to phosphorylation of the NMDAR by PKC (5), suggesting that PKC indirectly exerts its effect through interaction with NMDAR-associated signaling and/or trafficking protein(s) (3, 4). Very recently, two elegant studies revealed that a SNARE protein, either SNAP-23 or SNAP-25, is such an NMDAR-associated trafficking protein that is critical to the promotion of NMDAR trafficking by PKC (6, 7). The PKC-dependent activation of the Src family of non-receptor protein kinases enhances NMDAR function mainly through increasing NMDAR channel gating (3, 8 -11). It is still uncertain, however, whether an NMDAR-associated signaling protein that interacts with PKC displays a similar enhancing effect in NMDAR trafficking.Numerous studies performed as early as the late 1980s support the idea of functional and positive cross-talk between CaMKII and PKC (12-15). One speculation based on these findings is that PKC and CaMKII act in series and share, at least partially, a common pathway by convergence in regulating certain common substrates. Interestingly, NMDAR could be such a common molecular target. Both PKC and CaMKII have phosphorylation sites on NMDAR. CaMKII is associated with both NR2A and NR2B NMDAR subunits (16 -18). PKC potentiates NMDAR gating and in turn enhances Ca 2ϩ influx and intracellular Ca 2ϩ /camodulin, which could trigger CaMKII autophosphorylation and increase association with NR2A and NR2B sub...

show abstract

Section: Src Signaling Pathway Is Not Required For Pkc-inducedmentioning

confidence: 87%

Protein Kinase C Promotes N-Methyl-d-aspartate (NMDA) Receptor Trafficking by Indirectly Triggering Calcium/Calmodulin-dependent Protein Kinase II (CaMKII) Autophosphorylation

Yan

Ren

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…We detected a significant increase in basal PKC activity in the supernatant fraction (177 ± 38% of control, n = 6; P < 0.05) and a statistically nonsignificant increase in the pellet fraction (132 ± 28% ofcontrol, n = 6; P > 0.05). These mechanism for PKC activation during LTP in the dentate gyrus (26). The results of the fractionation experiments suggested the possibility that some proteolytic activation of PKC might occur during LTP, resulting in a soluble active catalytic fragment of PKC (i.e., PKM; refs.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of protein kinase C activation during the induction and maintenance of long-term potentiation probed using a selective peptide substrate.

Klann

Chen

Sweatt

1993

Proc. Natl. Acad. Sci. U.S.A.

227

130

View full text Add to dashboard Cite

Previous reports using various protein kinase inhibitors have suggested that protein kinase activity is necessary for both the induction and maintenance of hippocampal long-term potentiation (LTP), a cellular phenomenon likely to contribute to mammalian memory formation. We designed and characterized a selective peptide substrate for protein kinase C (PKC), corresponding to amino acids 28 to 43 of the neuronal protein neurogranin, and used the substrate to obtain direct biochemical evidence for activation of PKC in both the induction and maintenance phases of LTP. As the effect cannot be accounted for by either of two well-known mechanisms for persistent PKC activation, membrane insertion, or proteolysis, the persistent activation of PKC in the maintenance phase of LTP appears to occur via another mechanism. The maintenance phase of LTP is associated with decrased immunoreactivity of PKC, an effect that can be reversed with phosphatase treatment. Thus, PKC appears to be both phosphorylated and persistently activated in the maintenance phase of LTP. benzamidine, aprotinin (100 ng/ml), leupeptin (100 ng/ml), 1 mM EDTA, and 1 mM EGTA. The amount of protein used for assays was 2-10 pg in Fig. 1

show abstract

“…Evaluation of the functions of the various PKCs is an active area of research, but it has been established that PKC plays important roles in the nervous system. For example, PKC is involved in the regulation or modulation of neurotransmitter release (4,5), synaptic and neuronal plasticity (6,7), neuronal ion channels (8), cerebral microvascular function (9), and cognition (10)(11)(12). Alterations in PKC-dependent phosphorylation have been found in the brains of patients with Alzheimer disease (13,14), suggesting that PKC may also be involved in the pathogenesis of neurodegenerative disease.…”

mentioning

confidence: 99%

Protein kinase C activity and the relations between blood lead and neurobehavioral function in lead workers.

Hwang

Lee

Bressler

et al. 2002

Environ Health Perspect

View full text Add to dashboard Cite

At picomolar concentrations, lead activates protein kinase C (PKC). This activation has been implicated in the neurotoxicity of lead. No prior study has evaluated the association of PKC activity with neurobehavioral function in humans. The purpose of this study was to determine whether PKC activity is associated with neurobehavioral function or modifies the relationship between blood lead levels and neurobehavioral test scores. In this cross-sectional study of 212 current lead workers in the Republic of Korea, we assessed blood lead levels, neurobehavioral test scores, and PKC activity. PKC activity was determined by measuring the levels of phosphorylation of three erythrocyte membrane proteins (spectrin and the 52-kDa and 48-kDa subunits of band 4.9), using an in vitro back-phosphorylation assay. When linear regression was used to control for confounding variables, blood lead was a significant predictor of decrements in performance on tests of psychomotor function, manual dexterity, and executive ability. In linear regression models, back-phosphorylation levels were not associated with neurobehavioral test scores, but when dichotomized at the median, back-phosphorylation levels modified the relationship between blood lead and test scores. For spectrin and the 52-kDa and 48-kDa subunits of band 4.9, 5, 2, and 5 of 14 interaction terms, respectively, had associated p-values less than 0.10, all with positive signs, indicating that blood lead was associated with worse test scores only in subjects with lower back-phosphorylation levels. These data indicate that blood lead levels are associated with decrements in neurobehavioral test scores, mainly in the domains of manual dexterity and psychomotor function, but only in subjects with lower in vitro back-phosphorylation levels, which is equivalent to higher in vivo PKC activity. We hypothesize that subjects with higher PKC activity in the presence of lead may be more susceptible to the health effects of lead.

show abstract

Translocation of Protein Kinase C Activity May Mediate Hippocampal Long-Term Potentiation

Cited by 526 publications

References 18 publications

Protein Kinase C Promotes N-Methyl-d-aspartate (NMDA) Receptor Trafficking by Indirectly Triggering Calcium/Calmodulin-dependent Protein Kinase II (CaMKII) Autophosphorylation

Protein Kinase C Promotes N-Methyl-d-aspartate (NMDA) Receptor Trafficking by Indirectly Triggering Calcium/Calmodulin-dependent Protein Kinase II (CaMKII) Autophosphorylation

Mechanism of protein kinase C activation during the induction and maintenance of long-term potentiation probed using a selective peptide substrate.

Protein kinase C activity and the relations between blood lead and neurobehavioral function in lead workers.

Contact Info

Product

Resources

About