Fig. 1— The calcineurin–NFAT (nuclear factor of activated T-cells)
pathway and its possible regulation by vasoactive intestinal peptide (VIP).
In resting cells, NFAT resides in the cytoplasm, where it is maintained in
a phosphorylated, inactive state. Stimulation of cell-surface receptors coupled
to phospholipase C (PLC) results in calcium mobilisation, initially
from intracellular stores, followed by influx of Ca2+ through
specialised voltage-dependent Ca2+ channels (VDCC)
and Ca2+ release-activated Ca2+ channels (CRAC).
Upon activation by Ca2+, the phosphatase calcineurin dephosphorylates
NFAT, triggering its activation and nuclear translocation. In the nucleus,
NFAT interacts with other transcription factors, including activator protein (AP)-1,
to stimulate gene expression. When NFAT is re-phosphorylated it is exported
back to the cytoplasm. The immunosuppressive drug cyclosporin A inhibits calcineurin
interactions with all its substrates, whereas VIVIT selectively inhibits NFAT
activation. VIP appears to inhibit this pathway, but its mechanism of action
has yet to be determined. IP3: inositol-1,4,5-triphosphate. Modified from 26.