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Updated: Aug 11, 2026
Measuring Fast Calcium Fluxes in Cardiomyocytes
Published on: November 29, 2011
Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression
L A Timmerman1, N A Clipstone, S N Ho
1Department of Developmental Biology, Stanford University School of Medicine, California 94305, USA.
Abstract:
Cells need to distinguish between transient Ca2+ signals that induce events such as muscle contraction, secretion, adhesion and synaptic transmission, and sustained Ca2+ signals that are involved in cell proliferation and differentiation. The latter class of events is blocked in lymphocytes by the immunosuppressive drugs cyclosporin A and FK506, which inhibit calcineurin, a Ca2+-activated serine/threonine phosphatase necessary for the nuclear import of NF-AT transcription factors. Here we report that sustained high concentrations of Ca2+, but not transient pulses, are required to maintain NF-AT transcription factors in the nucleus, where they participate in Ca2+-dependent induction of genes required for lymphocyte activation and proliferation. Furthermore, overexpression and constitutive nuclear localization of NF-AT, but not Jun, Fos, NF-kappaB, Oct or Ets family members, renders the interleukin-2 enhancer in Jurkat T lymphocytes resistant to FK506 and cyclosporin A. Thus a primary effect of these immunosuppressive reagents is to control the subcellular localization of the NF-AT family of transcription factors.
Insights
Sustained calcium signals, not transient ones, are crucial for maintaining nuclear NF-AT transcription factors, which are essential for lymphocyte activation. Immunosuppressive drugs like FK506 and cyclosporin A primarily control NF-AT
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Cells differentiate between transient and sustained calcium (Ca2+) signals.
- Sustained Ca2+ signals regulate cell proliferation and differentiation.
- Immunosuppressive drugs cyclosporin A and FK506 inhibit calcineurin, blocking nuclear import of NF-AT transcription factors.
Purpose of the Study:
- To investigate the role of sustained Ca2+ concentrations in NF-AT transcription factor nuclear localization.
- To determine the primary mechanism of action for immunosuppressive drugs FK506 and cyclosporin A on lymphocyte activation.
Main Methods:
- Utilizing Jurkat T lymphocytes.
- Overexpression and constitutive nuclear localization of transcription factors.
- Assessing resistance to FK506 and cyclosporin A.
Main Results:
- Sustained high Ca2+ concentrations, not transient pulses, maintain NF-AT transcription factors in the nucleus.
- NF-AT transcription factors are essential for Ca2+-dependent gene induction in lymphocytes.
- Constitutive nuclear NF-AT confers resistance to FK506 and cyclosporin A.
Conclusions:
- Sustained Ca2+ signaling is critical for lymphocyte proliferation via NF-AT.
- FK506 and cyclosporin A primarily exert immunosuppression by controlling NF-AT nuclear localization.
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