Literature DB >> 25231981

Nerve growth factor (NGF) regulates activity of nuclear factor of activated T-cells (NFAT) in neurons via the phosphatidylinositol 3-kinase (PI3K)-Akt-glycogen synthase kinase 3β (GSK3β) pathway.

Man-Su Kim1, Leonid P Shutov2, Aswini Gnanasekaran2, Zhihong Lin2, Jacob E Rysted2, Jason D Ulrich2, Yuriy M Usachev3.   

Abstract

The Ca(2+)/calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) plays an important role in regulating many neuronal functions, including excitability, axonal growth, synaptogenesis, and neuronal survival. NFAT can be activated by action potential firing or depolarization that leads to Ca(2+)/calcineurin-dependent dephosphorylation of NFAT and its translocation to the nucleus. Recent data suggest that NFAT and NFAT-dependent functions in neurons can also be potently regulated by NGF and other neurotrophins. However, the mechanisms of NFAT regulation by neurotrophins are not well understood. Here, we show that in dorsal root ganglion sensory neurons, NGF markedly facilitates NFAT-mediated gene expression induced by mild depolarization. The effects of NGF were not associated with changes in [Ca(2+)]i and were independent of phospholipase C activity. Instead, the facilitatory effect of NGF depended on activation of the PI3K/Akt pathway downstream of the TrkA receptor and on inhibition of glycogen synthase kinase 3β (GSK3β), a protein kinase known to phosphorylate NFAT and promote its nuclear export. Knockdown or knockout of NFATc3 eliminated this facilitatory effect. Simultaneous monitoring of EGFP-NFATc3 nuclear translocation and [Ca(2+)]i changes in dorsal root ganglion neurons indicated that NGF slowed the rate of NFATc3 nuclear export but did not affect its nuclear import rate. Collectively, our data suggest that NGF facilitates depolarization-induced NFAT activation by stimulating PI3K/Akt signaling, inactivating GSK3β, and thereby slowing NFATc3 export from the nucleus. We propose that NFAT serves as an integrator of neurotrophin action and depolarization-driven calcium signaling to regulate neuronal gene expression.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Entities:  

Keywords:  Calcineurin; Calcium; DRG Neurons; Glycogen Synthase Kinase 3 (GSK-3); NFAT Transcription Factor; NGF; Neurotrophin

Mesh:

Substances:

Year:  2014        PMID: 25231981      PMCID: PMC4223335          DOI: 10.1074/jbc.M114.587188

Source DB:  PubMed          Journal:  J Biol Chem        ISSN: 0021-9258            Impact factor:   5.157


  74 in total

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Authors:  J Zhu; F McKeon
Journal:  Nature       Date:  1999-03-18       Impact factor: 49.962

Review 2.  Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons.

Authors:  Alexei Verkhratsky
Journal:  Physiol Rev       Date:  2005-01       Impact factor: 37.312

3.  The transcription factor NFAT3 mediates neuronal survival.

Authors:  Alessandra B Benedito; Maria Lehtinen; Ramiro Massol; Ulisses Gazos Lopes; Tomas Kirchhausen; Anjana Rao; Azad Bonni
Journal:  J Biol Chem       Date:  2004-11-10       Impact factor: 5.157

4.  A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.

Authors:  Yousang Gwack; Sonia Sharma; Julie Nardone; Bogdan Tanasa; Alina Iuga; Sonal Srikanth; Heidi Okamura; Diana Bolton; Stefan Feske; Patrick G Hogan; Anjana Rao
Journal:  Nature       Date:  2006-03-01       Impact factor: 49.962

5.  ATP induces Ca2+ release from IP3-sensitive Ca2+ stores exclusively in large DRG neurones.

Authors:  N Svichar; A Shmigol; A Verkhratsky; P Kostyuk
Journal:  Neuroreport       Date:  1997-05-06       Impact factor: 1.837

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Authors:  C L Stucky; S A Thayer; V S Seybold
Journal:  Neuroscience       Date:  1996-10       Impact factor: 3.590

7.  Ca2+ influx in resting rat sensory neurones that regulates and is regulated by ryanodine-sensitive Ca2+ stores.

Authors:  Y M Usachev; S A Thayer
Journal:  J Physiol       Date:  1999-08-15       Impact factor: 5.182

8.  IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life.

Authors:  D C Molliver; D E Wright; M L Leitner; A S Parsadanian; K Doster; D Wen; Q Yan; W D Snider
Journal:  Neuron       Date:  1997-10       Impact factor: 17.173

9.  Akt-dependent potentiation of L channels by insulin-like growth factor-1 is required for neuronal survival.

Authors:  L A Blair; K K Bence-Hanulec; S Mehta; T Franke; D Kaplan; J Marshall
Journal:  J Neurosci       Date:  1999-03-15       Impact factor: 6.167

10.  Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3.

Authors:  C R Beals; C M Sheridan; C W Turck; P Gardner; G R Crabtree
Journal:  Science       Date:  1997-03-28       Impact factor: 47.728

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  24 in total

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2.  Prognostic value of members of NFAT family for pan-cancer and a prediction model based on NFAT2 in bladder cancer.

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Journal:  Aging (Albany NY)       Date:  2021-05-07       Impact factor: 5.682

3.  Selective export of autotaxin from the endoplasmic reticulum.

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Journal:  J Biol Chem       Date:  2017-03-15       Impact factor: 5.157

4.  NFAT5 protects astrocytes against oxygen-glucose-serum deprivation/restoration damage via the SIRT1/Nrf2 pathway.

Authors:  Xun Xia; Bo Qu; Yun-Ming Li; Li-Bin Yang; Ke-Xia Fan; Hui Zheng; Hai-Dong Huang; Jian-Wen Gu; Yong-Qin Kuang; Yuan Ma
Journal:  J Mol Neurosci       Date:  2016-11-12       Impact factor: 3.444

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Journal:  Prog Neurobiol       Date:  2017-01-18       Impact factor: 11.685

6.  Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

Authors:  Nathalie Alvarez-Ricartes; Patricia Oliveros-Matus; Cristhian Mendoza; Nelson Perez-Urrutia; Florencia Echeverria; Alexandre Iarkov; George E Barreto; Valentina Echeverria
Journal:  Mol Neurobiol       Date:  2018-02-27       Impact factor: 5.590

Review 7.  Possible actions of cannabidiol in obsessive-compulsive disorder by targeting the WNT/β-catenin pathway.

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Journal:  Mol Psychiatry       Date:  2021-04-09       Impact factor: 15.992

8.  Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line.

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Journal:  Cancer Sci       Date:  2015-07-14       Impact factor: 6.716

9.  Schwann Cell Expressed Nogo-B Modulates Axonal Branching of Adult Sensory Neurons Through the Nogo-B Receptor NgBR.

Authors:  Christoph Eckharter; Nina Junker; Lilli Winter; Irmgard Fischer; Barbara Fogli; Steffen Kistner; Kristian Pfaller; Binhai Zheng; Gerhard Wiche; Lars Klimaschewski; Rüdiger Schweigreiter
Journal:  Front Cell Neurosci       Date:  2015-11-23       Impact factor: 5.505

10.  Pancreatic stellate cells contribute pancreatic cancer pain via activation of sHH signaling pathway.

Authors:  Liang Han; Jiguang Ma; Wanxing Duan; Lun Zhang; Shuo Yu; Qinhong Xu; Jianjun Lei; Xuqi Li; Zheng Wang; Zheng Wu; Jason H Huang; Erxi Wu; Qingyong Ma; Zhenhua Ma
Journal:  Oncotarget       Date:  2016-04-05
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