Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 277, Issue 40, Pages 37756-37764Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M203596200
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Funding
- NHLBI NIH HHS [HL44455, HL07647-12, T32 HL/AR 07944, HL63722] Funding Source: Medline
- NIDDK NIH HHS [DDK53832] Funding Source: Medline
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The nuclear factor of activated T-cells (NFAT), originally identified in T-cells, has since been shown to play a role in mediating Ca2+-dependent gene transcription in diverse cell types outside of the immune system. We have previously shown that nuclear accumulation of NFATc3 is induced in ileal smooth muscle by platelet-derived growth factor in a manner that depends on Ca2+ influx through L-type, voltage-dependent Ca2+ channels. Here we show that NFATc3 is also the predominant NFAT isoform expressed in cerebral artery smooth muscle and is induced to accumulate in the nucleus by UTP and other G(q/11)-coupled receptor agonists. This induction is mediated by calcineurin and is, dependent on sarcoplasmic reticulum Ca2+ release through inositol 1,4,5-trisphosphate receptors and extracellular Ca2+ influx through L-type, voltage-dependent Ca2+ channels. Consistent with results obtained in ileal smooth muscle, depolarization-induced Ca2+ influx fails to induce NFAT nuclear accumulation in cerebral arteries. We also provide evidence that Ca2+ release by ryanodine receptors in the form of Ca2+ sparks may exert an inhibitory influence on UTP-induced NFATc3 nuclear accumulation and further suggest that UTP may act, in part, by inhibiting Ca2+ sparks. These results are consistent with a multifactorial regulation of NFAT nuclear accumulation in smooth muscle that is likely to involve several intracellular signaling pathways, including local effects of sarcoplasmic reticulum. Ca2+ release and effects attributable to global elevations in intracellular Ca2+.
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