title: 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.
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.
authors.affiliation: 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.kr.
authors.forename: Man-Su
authors.initials: MS
authors.lastname: Kim
authors.affiliation: From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and.
authors.forename: Leonid P
authors.initials: LP
authors.lastname: Shutov
authors.affiliation: From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and.
authors.forename: Aswini
authors.initials: A
authors.lastname: Gnanasekaran
authors.affiliation: From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lin
authors.affiliation: From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Rysted
authors.affiliation: From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Ulrich
authors.affiliation: From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and yuriy-usachev@uiowa.edu.
authors.forename: Yuriy M
authors.initials: YM
authors.lastname: Usachev
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050778:NFATC Transcription Factors; C445503:transcription factor NF-AT c3; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020917:Receptor, trkA; C494920:Akt1 protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D002118:Calcium
keywords: Calcineurin; Calcium; DRG Neurons; Glycogen Synthase Kinase 3 (GSK-3); NFAT Transcription Factor; NGF; Neurotrophin