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Regulation of brain-derived neurotrophic factor-mediated transcription of the immediate early gene Arc by intracellular calcium and calmodulin.

ABSTRACT: The induction of the immediate early gene Arc is strongly implicated in synaptic plasticity. Although the role of ERK has been demonstrated, the regulation of Arc expression is largely unknown. In this study, we investigated the major signaling pathways underlying brain-derived neurotrophic factor (BDNF)-mediated Arc transcription in cultured cortical neurons. The BDNF-stimulated Arc transcription was regulated solely by the Ras-Raf-MAPK signaling through ERK, but not by phosphoinositide 3-kinase (PI3K) and PLC-gamma activities. Although it was demonstrated that BDNF might promote calcium entry through calcium channels and NMDA receptors, chelating extracellular calcium with EGTA failed to block Arc transcription. In contrast, chelating intracellular calcium ([Ca(2+)](i)) by BAPTA-AM abolished BDNF-mediated Arc up-regulation. Surprisingly, BAPTA-AM did not block ERK activation, indicating that [Ca(2+)](i) and Ras-Raf-MAPK are not coupled, and the activation of ERK alone is not sufficient to up-regulate Arc transcription. Moreover, we found that inhibition of calmodulin (CaM) by W13 blocked both Arc transcription and ERK activation, revealing a Ca(2+)-independent function of CaM. These data suggested novel functions of [Ca(2+)](i) and CaM in BDNF signaling. Comparison of the Arc transcription profiles between Ca(2+)-stimulated and BDNF-stimulated neurons demonstrated that the regulatory mechanisms were distinctively tailored to the complex features of neuronal activity. Specifically, PI3K and CaM-dependent protein kinase (CaMK) activity were required for Ca(2+)-stimulated Arc transcription through regulating ERK signaling. Such cross-talks between PI3K, CaMK, and ERK was absent in BDNF-stimulated neurons.

SUBMITTER: Zheng F

PROVIDER: S-EPMC2628963 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Regulation of brain-derived neurotrophic factor-mediated transcription of the immediate early gene Arc by intracellular calcium and calmodulin.

Zheng Fei F Luo Yongneng Y Wang Hongbing H

Journal of neuroscience research 20090201 2

The induction of the immediate early gene Arc is strongly implicated in synaptic plasticity. Although the role of ERK has been demonstrated, the regulation of Arc expression is largely unknown. In this study, we investigated the major signaling pathways underlying brain-derived neurotrophic factor (BDNF)-mediated Arc transcription in cultured cortical neurons. The BDNF-stimulated Arc transcription was regulated solely by the Ras-Raf-MAPK signaling through ERK, but not by phosphoinositide 3-kinas ...[more]

PMID: 18798281

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Project description:Screening of cDNA expression libraries with labelled calmodulin (CaM) as a probe resulted in the isolation of cDNA encoding proteins designated CAMTA (for calmodulin-binding transcription activators). The Arabidopsis genome contains 6 members of this protein family (AtCAMTA1-6) all containing in addition to a defined CaM-binding domain a DNA-binding domain and ankyrin-repeat motifs. RT-PCR analysis revealed that all 6 genes are expressed in all organ throughout plant development. Therefore functional regulation of AtCAMTA proteins is likely mediated by second messengers (e.g. calcium/calmodulin signalling) and protein levels rather than by or in addition to gene expression levels. Based on domain organisation and sequence homologies we identified putative members of this protein family in C. elegans and in human. A yeast system was used to express chimeric fusion proteins comprised of the DNA-binding domain of the bacterial LexA protein with various segments of AtCAMTA1. This analysis revealed a distinct domain of AtCAMTA1 capable of activating transcription. Similar results were obtained with two human CAMTA homologues. To identify the gene targets of CAMTA proteins in Arabidopsiswe plan to analyse the transcriptome in loss_of_function and gain_of_function AtCAMTA mutants. For this we have already isolated a T-DNA insertion mutant of AtCAMTA1 (two alleles) and have requested two other insertion mutants of AtCAMTA2 and AtCAMTA3 identified in other labs. Screening for insertion mutants in the three remaining genes is underway. In addition we have initiated a gain_of_function approach in which DL10 proteins are expressed under the control of the dexamethasone-inducible promoter. Genes whose expression will be found modulated in the mutant plants will be considered candidate targets of AtCAMTA proteins. This analysis will complement an in vitro study of DNA-protein interactions to identify target-binding sites (part of the BBSRC funded project). As a first step in the project proposed to GARNet we suggest to compare the transcriptome in WT whole plants (2 weeks old) with that of three T-DNA insertion AtCAMTA mutants and one line expressing AtCAMTA1 under the control of an inducible promoter. Keywords: strain_or_line_design

Dataset Information

Regulation of brain-derived neurotrophic factor-mediated transcription of the immediate early gene Arc by intracellular calcium and calmodulin.

Publications

Regulation of brain-derived neurotrophic factor-mediated transcription of the immediate early gene Arc by intracellular calcium and calmodulin.

Similar Datasets

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