Journal article
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
The Journal of biological chemistry, Vol.289(45), pp.31349-31360
11/07/2014
DOI: 10.1074/jbc.M114.587188
PMCID: PMC4223335
PMID: 25231981
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.
Details
- Title: Subtitle
- 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
- Creators
- Man-Su Kim - From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and the College of Pharmacy, Inje University, Gimhae 621-749, Korea mansu-kim@inje.ac.krLeonid P Shutov - From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 andAswini Gnanasekaran - From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 andZhihong Lin - From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 andJacob E Rysted - From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 andJason D Ulrich - From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 andYuriy M Usachev - From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and yuriy-usachev@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.289(45), pp.31349-31360
- DOI
- 10.1074/jbc.M114.587188
- PMID
- 25231981
- PMCID
- PMC4223335
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- United States
- Grant note
- NS087068 / NINDS NIH HHS R01 NS087068 / NINDS NIH HHS R01 NS072432 / NINDS NIH HHS NS072432 / NINDS NIH HHS
- Language
- English
- Date published
- 11/07/2014
- Academic Unit
- Iowa Neuroscience Institute; Anesthesia; Neuroscience and Pharmacology
- Record Identifier
- 9984040354202771
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