Antisense GAP‐43 Inhibits the Evoked Release of Dopamine from PC12 Cells

Ivins, Kathryn J.; Neve, Kim A.; Feller, Daniel; Fidel, Seth; Neve, Rachael L.

doi:10.1111/j.1471-4159.1993.tb03194.x

Cited by 71 publications

(34 citation statements)

References 37 publications

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“…15 We have previously shown that GAP-43 mRNA is highly expressed in monoaminergic neurons of adult rat brain 16 and phosphorylation of this protein has been linked to monoamine release. [17][18][19] We also found a high expression of GAP-43 mRNA in the limbic system of the adult rat including the amygdala and neo-cortex. 20 Similarly, in human brain, the transcript of GAP-43 is enriched in the cortex and limbic system.…”

Section: Introductionmentioning

confidence: 68%

“…In fact, there is some evidence showing that reduction of GAP-43 inhibits the release of noradrenaline from cerebrocortical synapto-somes 17 and of dopamine from permeated synaptosomes 18 and P12 cells. 19 Although there are no data with respect to 5-HT release, one can hypothesize a similar involvement of GAP-43 in this monoaminergic system.…”

Section: Discussionmentioning

confidence: 98%

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Growth-associated protein (GAP-43), its mRNA, and protein kinase C (PKC) isoenzymes in brain regions of depressed suicides

Hrdina

Faludi

et al. 1998

Mol Psychiatry

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The aim of this study was to investigate whether the previously observed adaptive changes in the monoaminergic receptors in post-mortem brains of depressed suicide victims are associated with alteration in some functional proteins involved in serotonergic neuronal signalling, namely PKC and GAP-43. Selected regions from ten brains of antidepressant-free depressed suicide victims and ten matched controls were used to examine the levels of GAP-43 protein, GAP-43 mRNA and PKC isoenzymes by Western blotting with monoclonal antibodies specific for these proteins. A major finding of the study was a significant decrease in GAP-43 protein levels and its mRNA expression in prefrontal cortex (BA9) (by 24% and 34%, respectively) of suicide brains compared to controls. No significant changes were found in GAP-43 protein or its mRNA in frontopolar cortex (BA10), amygdala, substantia nigra or putamen. Levels of PKC isoenzymes had a heterogenous regional distribution but were not significantly altered in any of the regions examined. Given the role of GAP-43 in the establishment and reorganization of synaptic connections, the finding of selective reduction of this protein in prefrontal cortex suggests that a dysfunctional synaptic organization in this region may be associated with depression and suicidal behaviour. This study provides the first evidence of an alteration in a protein related to the neuronal plasticity in the brain of depressed suicide victims.

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Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 98%

Growth-associated protein (GAP-43), its mRNA, and protein kinase C (PKC) isoenzymes in brain regions of depressed suicides

Hrdina

Faludi

et al. 1998

Mol Psychiatry

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“…Concerning transmitter function, phosphorylation of GAP-43 has been correlated with enhanced release (De Graan et al 1990b;Dekker et al 1990;Iannazzo 2001); overexpressing phosphorylatable GAP-43 in the presynaptic terminal is likely to alter this cellular function. Reductions in Ca ++ -evoked neurotransmitter release have been observed after levels of GAP-43 were reduced using antibodies (Hens et al 1995(Hens et al , 1998 or antisense oligonucleotides (Ivins et al 1993). Elevated GAP-43 transgene expression in hippocampal granule cells and protein in the mossy fiber terminal fields could thus enhance signal propagation through the hippocampal network, ultimately leading to enhanced memory function in these animals.…”

Section: Discussionmentioning

confidence: 99%

GAP-43 gene expression regulates information storage

Holahan¹,

Honegger²,

Tabatadze³

et al. 2007

Learn. Mem.

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Previous reports have shown that overexpression of the growth-and plasticity-associated protein GAP-43 improves memory. However, the relation between the levels of this protein to memory enhancement remains unknown. Here, we studied this issue in transgenic mice (G-Phos) overexpressing native, chick GAP-43. These G-Phos mice could be divided at the behavioral level into "spatial bright" and "spatial dull" groups based on their performance on two hidden platform water maze tasks. G-Phos dull mice showed both acquisition and retention deficits on the fixed hidden platform task, but were able to learn a visible platform task. G-Phos bright mice showed memory enhancement relative to wild type on the more difficult movable hidden platform spatial memory task. In the hippocampus, the G-Phos dull group showed a 50% greater transgenic GAP-43 protein level and a twofold elevated transgenic GAP-43 mRNA level than that measured in the G-Phos bright group. Unexpectedly, the dull group also showed an 80% reduction in hippocampal Tau1 staining. The high levels of GAP-43 seen here leading to memory impairment find its histochemical and behavioral parallel in the observation of Rekart et al. (Neuroscience 126 126: 579-584) who described elevated levels of GAP-43 protein in the hippocampus of Alzheimer's patients. The present data suggest that moderate overexpression of a phosphorylatable plasticity-related protein can enhance memory, while excessive overexpression may produce a "neuroplasticity burden" leading to degenerative and hypertrophic events culminating in memory dysfunction.The growth-and plasticity-associated protein, GAP-43, plays a central role in the learning and memory process. GAP-43 is neuron-specific (Chan et al. 1986;Basi et al. 1987;Alexander et al. 1988;Liu and Storm 1989;Skene and Virag 1989;Zuber et al. 1989;Nielander et al. 1990), is found in high concentrations in growth cones (Nelson et al. 1989), and is closely associated with regenerative and developmental growth (Skene 1989;Strittmatter et al. 1995). Its activity is regulated by a protein kinase C (PKC) phosphorylation site (Alexander et al. 1988;De Graan et al. 1990a) embedded within a calmodulin-binding domain (Alexander et al. 1988) that exist in a yin-yang relation. GAP-43 demonstrates a direct relation between its phosphorylation state and enhancement of LTP (Lovinger et al. 1985(Lovinger et al. , 1986Lovinger and Routtenberg 1988;Gianotti et al. 1992) as well as behavioral learning (Routtenberg and Ehrlich 1975;Ehrlich et al. 1977;Cammarota et al. 1997;Young et al. 2000Young et al. , 2002, suggesting a pivotal role for this presynaptic protein in mnemonic function (for reviews, see Routtenberg 1987, 1997;Perrone Bizzozero and Tanner 2006).Transgenic overexpression of the phosphorylatable (GPhos), but not the nonphosphorylatable (G-NonP) or permanently (pseudo)phosphorylated (G-Perm), form of GAP-43 in mice enhanced memory on a radial arm maze task (Routtenberg et al. 2000). This selective enhancement demonstrated that the PKC phosphorylation s...

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“…After synaptogenesis, GAP-43 expression declines sharply in most neuronal populations except for those in specific association areas in the neocortex and limbic system Neve et al, 1988). GAP-43 is known to participate both in mechanisms of axonal pathfinding during neural development and in the regulation of neurotransmitter release and synaptic plasticity in mature synapses (Dekker et al, 1989;Aigner and Caroni, 1993;Ivins et al, 1993;Meberg et al, 1995;Strittmatter et al, 1995). Given the important biological properties of this protein, it is of great interest to define the mechanisms that control the developmental pattern and regional variations in GAP-43 gene expression.…”

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confidence: 99%

Post-Transcriptional Regulation of the GAP-43 Gene by Specific Sequences in the 3′ Untranslated Region of the mRNA

et al. 1997

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We have shown previously that GAP-43 gene expression during neuronal differentiation is controlled by selective changes in mRNA stability. This process was found to depend on highly conserved sequences in the 3Ј untranslated region (3Ј UTR) of the mRNA. To map the sequences in the GAP-43 3Ј UTR that mediate this post-transcriptional event, we generated specific 3Ј UTR deletion mutants and chimeras with the ␤-globin gene and measured their half-lives in transfected PC12 cells. Our results indicate that there are two distinct instability-conferring elements localized at the 5Ј and 3Ј ends of the GAP-43 3Ј UTR. Of these destabilizing elements, only the one at the 3Ј end is required for the stabilization of the mRNA in response to treatment with the phorbol ester TPA. This 3Ј UTR element consists of highly conserved uridine-rich sequences and contains specific recognition sites for two neural-specific GAP-43 mRNAbinding proteins. Analysis of the levels of mRNA and protein derived from various 3Ј UTR deletion mutants indicated that all mutants were translated effectively and that differences in gene expression in response to TPA were attributable to changes in GAP-43 mRNA stability. In addition, the phorbol ester was found to affect the binding of specific RNA-binding proteins to the 3Ј UTR of the GAP-43 mRNA. Given that, like the GAP-43 mRNA, its degradation machinery and the GAP-43 mRNAbinding proteins are expressed primarily in neural cells, we propose that these factors may be involved in the posttranscriptional regulation of GAP-43 gene expression during neuronal differentiation.

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Antisense GAP‐43 Inhibits the Evoked Release of Dopamine from PC12 Cells

Cited by 71 publications

References 37 publications

Growth-associated protein (GAP-43), its mRNA, and protein kinase C (PKC) isoenzymes in brain regions of depressed suicides

Growth-associated protein (GAP-43), its mRNA, and protein kinase C (PKC) isoenzymes in brain regions of depressed suicides

GAP-43 gene expression regulates information storage

Post-Transcriptional Regulation of the GAP-43 Gene by Specific Sequences in the 3′ Untranslated Region of the mRNA

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