Protein kinase C in synaptic plasticity: Changes in the in situ phosphorylation state of identified pre- and postsynaptic substrates

Ramakers, G.J.A.; Pasinelli, Piera; Hens, Jacques J. H.; Gispen, Willem Hendrik; Graan, P.N.E. de

doi:10.1016/s0278-5846(97)00013-4

Cited by 67 publications

(34 citation statements)

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“…Furthermore, downstream of C a 2ϩ influx second messenger systems such as protein kinase C (PKC) (Ghiradi et al, 1992;Parfitt and Madison, 1993;C apogna et al, 1995; C arroll et al, 1998;Stevens and Sullivan, 1998) and cAM P-dependent protein kinase A (PKA) (Chavez-Noriega and Stevens, 1994; Kondo and Marty, 1997; Chen and Regehr, 1997) have been implicated in the regulation of miniature activity. Both PK A (Ghiradi et al, 1992;Hell et al, 1995;Tong et al, 1996) and PKC (for review, see Ramakers et al, 1997;Majewski and Iannazzo, 1998) have also been shown to regulate action potential (AP)-dependent transmitter release.Unlike (AP-) evoked transmitter release (Haage et al, 1998), continued miniature release is apparently mediated by lowthreshold rather than high-threshold voltage-gated calcium channels (VGCCs) (Parfitt and Madison, 1993;Momiyama and Takahashi, 1994;Scanziani et al, 1995;Bao et al, 1998). Although different channels may control AP-evoked and spontaneous release, there is good evidence that miniature and evoked release can be regulated in parallel at presynaptic terminals of the mammalian nervous system.…”

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confidence: 99%

Correlation of Miniature Synaptic Activity and Evoked Release Probability in Cultures of Cortical Neurons

Prange

Murphy

1999

J. Neurosci.

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Spontaneous miniature synaptic activity is caused by action potential (AP)-independent release of transmitter vesicles and is regulated at the level of single synapses. In cultured cortical neurons we have used this spontaneous vesicle turnover to load the styryl dye FM1-43 into synapses with high rates of miniature synaptic activity. Automated selection procedures restricted analysis to synapses with sufficient levels of miniature activity-mediated FM1-43 uptake. After FM1-43 loading, vesicular FM1-43 release in response to AP stimulation was recorded at single synapses as a measure of release probability. We find that synapses with high rates of miniature activity possess significantly enhanced evoked release rates compared with a control population. Because the difference in release rates between the two populations is [Ca 2ϩ ] o -dependent, it is most likely caused by a difference in release probability. Within the subpopulation of synapses with high miniature activity, we find that the probabilities for miniature and AP-evoked release are correlated at single synaptic sites. Furthermore, the degree of miniature synaptic activity is correlated with the vesicle pool size. These findings suggest that both evoked and miniature vesicular release are regulated in parallel and that the frequency of miniature synaptic activity can be used as an indicator for evoked release efficacy.Key words: miniature; evoked; synapse; vesicle; release; probability; pool size; calcium Spontaneous miniature synaptic activity exists throughout the vertebrate nervous system. Miniature activity is attributed to spontaneous AP-independent presynaptic release of one (Frerking et al., 1997) or more (Vautrin and Barker, 1995;Wall and Usowicz, 1998) transmitter quanta. Findings from our laboratory using postsynaptic imaging of miniature activity indicate that the probability for miniature release is highly variant between synapses even on the same dendrite (Murphy et al., 1994(Murphy et al., , 1995Wang et al., 1999). This variability among synapses indicates that miniature release can be regulated on the level of individual synapses. It has been shown that [C a 2ϩ ] i influences the frequency of miniature activity in C NS (Minota et al., 1991;Doze et al., 1995;Scanziani et al., 1995;C apogna et al., 1996aPoisbeau et al., 1996;Schoppa and Westbrook, 1997;Bao et al., 1998;Li et al., 1998) and peripheral nervous system (PNS) (Matthews and Wickelgren, 1977;Marcus et al., 1992;Katz et al., 1995). Furthermore, downstream of C a 2ϩ influx second messenger systems such as protein kinase C (PKC) (Ghiradi et al., 1992;Parfitt and Madison, 1993;C apogna et al., 1995; C arroll et al., 1998;Stevens and Sullivan, 1998) and cAM P-dependent protein kinase A (PKA) (Chavez-Noriega and Stevens, 1994; Kondo and Marty, 1997; Chen and Regehr, 1997) have been implicated in the regulation of miniature activity. Both PK A (Ghiradi et al., 1992;Hell et al., 1995;Tong et al., 1996) and PKC (for review, see Ramakers et al., 1997;Majewski and Iannazzo, 1998) have ...

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Correlation of Miniature Synaptic Activity and Evoked Release Probability in Cultures of Cortical Neurons

Prange

Murphy

1999

J. Neurosci.

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“…The acidic, calmodulinbinding PKC substrate RC3 (also called neurogranin), is a likely substrate for PKC␥ because the two proteins colocalize in the dendrites of excitatory neurons of the cerebral cortex, hippocampus, and striatum and are expressed at the same stages of development (4 -6). Additionally, RC3 is phosphorylated during LTP and dephosphorylated during LTD, and antibodies to RC3 interfere with the induction of LTP (7)(8)(9). Here, we examine the incorporation of 32 PO 4 into RC3 and two other major PKC substrates; GAP-43/B-50 and MARCKS by quantitative immunoprecipitation (8) before and after treating hippocampal slices from PKC␥-deficient and wild-type mice with potassium, glutamate, or the phorbol ester 4␣-phorbol 12,13-dibutyrate (PDB).…”

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Substrate Phosphorylation in the Protein Kinase Cγ Knockout Mouse

Ramakers

Gerendasy

Graan

1999

Journal of Biological Chemistry

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The phosphorylation state of three identified neuralspecific protein kinase C substrates (RC3, GAP-43/B-50, and MARCKS) was monitored in hippocampal slices of mice lacking the ␥-subtype of protein kinase C and wildtype controls by quantitative immunoprecipitation following 32 P i labeling. Depolarization with potassium, activation of glutamate receptors with glutamate, or direct stimulation of protein kinase C with a phorbol ester increased RC3 phosphorylation in wild-type animals but failed to affect RC3 phosphorylation in mice lacking the ␥-subtype of protein kinase C. Our results suggests the following biochemical pathway: activation of a postsynaptic (metabotropic) glutamate receptor stimulates the ␥-subtype of protein kinase C, which in turn phosphorylates RC3. The inability to increase RC3 phosphorylation in mice lacking the ␥-subtype of protein kinase C by membrane depolarization or glutamate receptor activation may contribute to the spatial learning deficits and impaired hippocampal LTP observed in these mice.Mice lacking the ␥-subtype of protein kinase C (PKC␥) 1 show mild spatial learning deficits and exhibit impaired hippocampal long term potentiation (LTP), suggesting that PKC␥ is a key regulatory component in LTP and spatial memory (1-3). However, the biochemical pathways that are perturbed in these mice have not yet been identified. The acidic, calmodulinbinding PKC substrate RC3 (also called neurogranin), is a likely substrate for PKC␥ because the two proteins colocalize in the dendrites of excitatory neurons of the cerebral cortex, hippocampus, and striatum and are expressed at the same stages of development (4 -6). Additionally, RC3 is phosphorylated during LTP and dephosphorylated during LTD, and antibodies to RC3 interfere with the induction of LTP (7-9). Here, we examine the incorporation of 32 PO 4 into RC3 and two other major PKC substrates; GAP-43/B-50 and MARCKS by quantitative immunoprecipitation (8) before and after treating hippocampal slices from PKC␥-deficient and wild-type mice with potassium, glutamate, or the phorbol ester 4␣-phorbol 12,13-dibutyrate (PDB). We show that stimuli that readily increase RC3 phosphorylation in wild-type mice fail to affect RC3 phosphorylation in PKC␥-deficient mice. EXPERIMENTAL PROCEDURESThe effects of depolarization, glutamate receptor stimulation, and direct PKC activation were determined in PKC␥ knockout and litter mate control mice (bred into a C57/Bl background for six generations and kindly provided to us by Dr. J. M. Wehner).For Western blotting, the forebrain of each mouse was homoginized in 10 ml of buffer containing 50 mM Tris (pH 7.5), 100 mM NaCl, 2 mM EDTA, 1 mM EGTA, 50 mM dithiothreitol, 0.6 mM phenylmethylsulfonyl fluoride, and 1% SDS. We equalized the protein concentrations of the homogenates based on three independent protein assays performed in triplicate prior to adding SDS and dithiothreitol using the BCA method and then immuno-blotted serial dilutions of each homogenate. The blotts were probed with polyclonal rabbit anti-RC3 (Aff...

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“…Various isozymes of PKC are involved in the formation of LTP. For instance, a null mutation in PKC-γ prevented the induction of LTP [233]. PKC is activated postsynaptically when metabotropic glutamate receptors (mGluR) are activated leading to the formation of DAG and release of intracellular Ca 2+ , which activates PKC.…”

Section: Protein Kinase C (Pkc)mentioning

confidence: 99%

Metal toxicity at the synapse: presynaptic, postsynaptic and long-term effects

Ghazala

Sadiq

Chowdhury

et al. 2010

Qatar Foundation Annual Research Forum Proceedings

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Metal neurotoxicity is a global health concern. This paper summarizes the evidence for metal interactions with synaptic transmission and synaptic plasticity. Presynaptically metal ions modulate neurotransmitter release through their interaction with synaptic vesicles, ion channels, and the metabolism of neurotransmitters (NT). Many metals (e.g., Pb 2+ , Cd 2+ , and Hg + ) also interact with intracellular signaling pathways. Postsynaptically, processes associated with the binding of NT to their receptors, activation of channels, and degradation of NT are altered by metals. Zn 2+ , Pb 2+ , Cu 2+ , Cd 2+ , Ni 2+ , Co 2+ , Li 3+ , Hg + , and methylmercury modulate NMDA, AMPA/kainate, and/or GABA receptors activity. Al 3+ , Pb 2+ , Cd 2+ , and As 2 O 3 also impair synaptic plasticity by targeting molecules such as CaM, PKC, and NOS as well as the transcription machinery involved in the maintenance of synaptic plasticity. The multiple effects of metals might occur simultaneously and are based on the specific metal species, metal concentrations, and the types of neurons involved.

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Protein kinase C in synaptic plasticity: Changes in the in situ phosphorylation state of identified pre- and postsynaptic substrates

Cited by 67 publications

References 163 publications

Correlation of Miniature Synaptic Activity and Evoked Release Probability in Cultures of Cortical Neurons

Correlation of Miniature Synaptic Activity and Evoked Release Probability in Cultures of Cortical Neurons

Substrate Phosphorylation in the Protein Kinase Cγ Knockout Mouse

Metal toxicity at the synapse: presynaptic, postsynaptic and long-term effects

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