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This Article Full Text Full Text (PDF) All Versions of this Article: 579/2/535    most recent jphysiol.2006.120048v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shen, T. Articles by Schneider, M. F. Search for Related Content PubMed PubMed Citation Articles by Shen, T. Articles by Schneider, M. F. Related Collections Skeletal Muscle and Exercise

¹ Departments of Biochemistry and Molecular Biology
² Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA

The transcription factor nuclear factor of activated T cells (NFAT)c1 has been shown to be involved in turning on slow skeletal muscle fibre gene expression. Previous studies from our laboratory have characterized the stimulation pattern-dependent nuclear import and resting shuttling of NFATc1–green fluorescent protein (GFP) in flexor digitorum brevis (FDB) muscle fibres from adult mouse. In this study, we use viral expression of the transcription factor NFATc1–GFP fusion protein to investigate the mechanisms underlying the nuclear export of the NFATc1–GFP that accumulated in the nuclei of cultured dissociated adult mouse FDB muscle fibres during slow-twitch fibre type electrical stimulation. In these studies, we found that inhibition of either glycogen synthase kinase 3 (GSK3) or casein kinase 1 or 2 (CK1/2) markedly slowed the decay of nuclear NFATc1–GFP after cessation of muscle fibre electrical stimulation, whereas inhibition of casein kinase 1, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase and protein kinase A had little effect. Simultaneous inhibition of GSK3 and CK1/2 completely blocked the nuclear export of NFATc1–GFP after muscle activity. We also developed a simplified model of NFATc1 phosphorylation/dephosphorylation and nuclear fluxes, and used this model to simulate the observed time courses of nuclear NFATc1–GFP with and without NFATc1 kinase inhibition. Our results suggest that GSK3 and CK1/2 are the major protein kinases that contribute to the removal of NFATc1 that accumulates in muscle fibre nuclei during muscle activity, and that GSK3 and CK1/2 are responsible for phosphorylating NFATc1 in muscle nuclei in a complementary or synergistic fashion.

(Received 25 August 2006; accepted after revision 20 December 2006; first published online 21 December 2006)
Corresponding author M. F. Schneider: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD 21201-1503, USA. Email: mschneid{at}umaryland.edu

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