Opposing actions of inositol 1,4,5-trisphosphate and ryanodine receptors on nuclear factor of activated T-cells regulation in smooth muscle.
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+).
Gomez
Maria F
MF
Department of Pharmacology, University of Vermont, Burlington, Vermont 05405, USA.
Stevenson
Andra S
AS
Bonev
Adrian D
AD
Hill-Eubanks
David C
DC
Nelson
Mark T
MT
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000077214:Becaplermin; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002536:Cerebral Arteries / Q000502:physiology; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000502:physiology*; D050778:NFATC Transcription Factors; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D020239:Receptor Cross-Talk / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014544:Uridine Triphosphate / Q000494:pharmacology
D015220:Calcium Channels; D017931:DNA Primers; D004268:DNA-Binding Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D020574:Proto-Oncogene Proteins c-sis; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D014157:Transcription Factors; C445503:transcription factor NF-AT c3; D000077214:Becaplermin; D004815:Epidermal Growth Factor; D014544:Uridine Triphosphate