PMID- 22977251 OWN - NLM STAT- MEDLINE DCOM- 20130123 LR - 20211021 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 287 IP - 45 DP - 2012 Nov 2 TI - Distinct activation properties of the nuclear factor of activated T-cells (NFAT) isoforms NFATc3 and NFATc4 in neurons. PG - 37594-609 LID - 10.1074/jbc.M112.365197 [doi] AB - The Ca(2+)/calcineurin-dependent transcription factor NFAT (nuclear factor of activated T-cells) is implicated in regulating dendritic and axonal development, synaptogenesis, and neuronal survival. Despite the increasing appreciation for the importance of NFAT-dependent transcription in the nervous system, the regulation and function of specific NFAT isoforms in neurons are poorly understood. Here, we compare the activation of NFATc3 and NFATc4 in hippocampal and dorsal root ganglion neurons following electrically evoked elevations of intracellular Ca(2+) concentration ([Ca(2+)](i)). We find that NFATc3 undergoes rapid dephosphorylation and nuclear translocation that are essentially complete within 20 min, although NFATc4 remains phosphorylated and localized to the cytosol, only exhibiting nuclear localization following prolonged (1-3 h) depolarization. Knocking down NFATc3, but not NFATc4, strongly diminished NFAT-mediated transcription induced by mild depolarization in neurons. By analyzing NFATc3/NFATc4 chimeras, we find that the region containing the serine-rich region-1 (SRR1) mildly affects initial NFAT translocation, although the region containing the serine-proline repeats is critical for determining the magnitude of NFAT activation and nuclear localization upon depolarization. Knockdown of glycogen synthase kinase 3beta (GSK3beta) significantly increased the depolarization-induced nuclear localization of NFATc4. In contrast, inhibition of p38 or mammalian target of rapamycin (mTOR) kinases had no significant effect on nuclear import of NFATc4. Thus, electrically evoked [Ca(2+)](i) elevation in neurons rapidly and strongly activates NFATc3, whereas activation of NFATc4 requires a coincident increase in [Ca(2+)](i) and suppression of GSK3beta, with differences in the serine-proline-containing region giving rise to these distinct activation properties of NFATc3 and NFATc4. FAU - Ulrich, Jason D AU - Ulrich JD AD - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. FAU - Kim, Man-Su AU - Kim MS FAU - Houlihan, Patrick R AU - Houlihan PR FAU - Shutov, Leonid P AU - Shutov LP FAU - Mohapatra, Durga P AU - Mohapatra DP FAU - Strack, Stefan AU - Strack S FAU - Usachev, Yuriy M AU - Usachev YM LA - eng GR - R01 NS043254/NS/NINDS NIH HHS/United States GR - NS054614/NS/NINDS NIH HHS/United States GR - R01 NS054614/NS/NINDS NIH HHS/United States GR - R01 NS056244/NS/NINDS NIH HHS/United States GR - NS056244/NS/NINDS NIH HHS/United States GR - NS072432/NS/NINDS NIH HHS/United States GR - NS043254/NS/NINDS NIH HHS/United States GR - R01 NS069898/NS/NINDS NIH HHS/United States GR - F31 MH081420/MH/NIMH NIH HHS/United States GR - T32 GM067795/GM/NIGMS NIH HHS/United States GR - R01 NS072432/NS/NINDS NIH HHS/United States GR - NS069898/NS/NINDS NIH HHS/United States GR - R56 NS056244/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20120912 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (NFATC Transcription Factors) RN - 0 (transcription factor NF-AT c3) RN - 147336-22-9 (Green Fluorescent Proteins) RN - EC 2.7.11.1 (GSK3B protein, human) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, rat) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - SY7Q814VUP (Calcium) SB - IM MH - Active Transport, Cell Nucleus MH - Animals MH - Animals, Newborn MH - Calcium/*metabolism MH - Cell Nucleus/metabolism MH - Cells, Cultured MH - Cytosol/metabolism MH - Electric Stimulation MH - Ganglia, Spinal/cytology/metabolism MH - Glycogen Synthase Kinase 3/genetics/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Green Fluorescent Proteins/genetics/metabolism MH - Hippocampus/cytology/metabolism MH - Humans MH - Immunoblotting MH - Microscopy, Confocal MH - NFATC Transcription Factors/genetics/*metabolism MH - Neurons/*metabolism MH - PC12 Cells MH - Phosphorylation MH - RNA Interference MH - Rats MH - Rats, Sprague-Dawley MH - Time Factors MH - Transcription, Genetic PMC - PMC3488037 EDAT- 2012/09/15 06:00 MHDA- 2013/01/24 06:00 PMCR- 2013/11/02 CRDT- 2012/09/15 06:00 PHST- 2012/09/15 06:00 [entrez] PHST- 2012/09/15 06:00 [pubmed] PHST- 2013/01/24 06:00 [medline] PHST- 2013/11/02 00:00 [pmc-release] AID - S0021-9258(20)62392-4 [pii] AID - M112.365197 [pii] AID - 10.1074/jbc.M112.365197 [doi] PST - ppublish SO - J Biol Chem. 2012 Nov 2;287(45):37594-609. doi: 10.1074/jbc.M112.365197. Epub 2012 Sep 12.