title: Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca2+Signals.
abstract: Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes. How closely related coexpressed transcription factors are differentially activated remains unclear. Here, we show that two Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3and Ca2+signals for physiologically sustained activation. NFAT1 is stimulated by sub-plasmalemmal Ca2+microdomains, whereas NFAT4 additionally requires Ca2+mobilization from the inner nuclear envelope by nuclear InsP3receptors. NFAT1 is rephosphorylated (deactivated) more slowly than NFAT4 in both cytoplasm and nucleus, enabling a more prolonged activation phase. Oscillations in cytoplasmic Ca2+, long considered the physiological form of Ca2+signaling, play no role in activating either NFAT protein. Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca2+. Our results show how gene expression can be controlled by coincident yet geographically distinct Ca2+signals, generated by a freely diffusible InsP3message.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Pulak
authors.initials: P
authors.lastname: Kar
authors.affiliation: Computational Biology, Department of Computer Science, University of Oxford, Parks Road, Oxford, OX1 3QD, UK.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Mirams
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Christian
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK. Electronic address: anant.parekh@dpag.ox.ac.uk.
authors.forename: Anant B
authors.initials: AB
authors.lastname: Parekh
mesh_terms: D000818:Animals; D001491:Basophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism*; D017997:Leukotriene C4 / Q000494:pharmacology; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007295:Inositol Phosphates; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494008:NFATC3 protein, human; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D017997:Leukotriene C4; C092449:inositol 1,2,3-trisphosphate; D019284:Thapsigargin; D002118:Calcium