Abstract
The nuclear factor of activated T-cells (NFAT), originally identified in T-cells, has since been shown to play a role in mediating Ca(2+)-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 Ca(2+) influx through L-type, voltage-dependent Ca(2+) 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 Ca(2+) release through inositol 1,4,5-trisphosphate receptors and extracellular Ca(2+) influx through L-type, voltage-dependent Ca(2+) channels. Consistent with results obtained in ileal smooth muscle, depolarization-induced Ca(2+) influx fails to induce NFAT nuclear accumulation in cerebral arteries. We also provide evidence that Ca(2+) release by ryanodine receptors in the form of Ca(2+) sparks may exert an inhibitory influence on UTP-induced NFATc3 nuclear accumulation and further suggest that UTP may act, in part, by inhibiting Ca(2+) 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 Ca(2+) release and effects attributable to global elevations in intracellular Ca(2+).
Highlights
Nuclear factor of activated T-cells (NFAT)1 was originally identified as the transcription factor responsible for mediating the Ca2ϩ-dependent transcription of genes involved in T-cell activation [1, 2] but has since been shown to play a role in mediating Ca2ϩ-dependent gene transcription in diverse cell types outside of the immune system, including neurons [3], endothelial cells [4, 5], cardiac muscle [6], skeletal muscle [7, 8], and smooth muscle [9, 10]
In contrast to the inhibitory effect that blockers of IP3 receptors (IP3R) exert on NFATc3 nuclear accumulation, we found that inhibition of ryanodine receptors (RyRs) with ryanodine potentiates UTP-induced NFATc3 nuclear translocation
We have shown that UTP and a number of other Gq/11coupled vasoconstrictor agonists effectively induce the nuclear accumulation of NFATc3 in cerebral artery smooth muscle
Summary
Nuclear factor of activated T-cells (NFAT)1 was originally identified as the transcription factor responsible for mediating the Ca2ϩ-dependent transcription of genes involved in T-cell activation [1, 2] but has since been shown to play a role in mediating Ca2ϩ-dependent gene transcription in diverse cell types outside of the immune system, including neurons [3], endothelial cells [4, 5], cardiac muscle [6], skeletal muscle [7, 8], and smooth muscle [9, 10]. We show that NFATc3 is the predominant NFAT isoform expressed in cerebral artery smooth muscle and is induced to accumulate in the nucleus by UTP and other Gq/11-coupled receptor agonists. In native cerebral artery smooth muscle cells, UTP and other Gq/11-coupled receptor agonists induce a calcineurin-mediated nuclear accumulation of NFATc3.
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