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InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase

Author

Listed:
  • Meredith C. Hermosura

    (Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine at The University of Hawaii)

  • Hiroshi Takeuchi

    (Laboratory of Molecular and Cellular Biochemistry, Graduate School of Dental Sciences, Kyushu University and Kyushu University Station for Collaborative Research)

  • Andrea Fleig

    (Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine at The University of Hawaii)

  • Andrew M. Riley

    (Wolfson Laboratory of Medicinal Chemistry, University of Bath)

  • Barry V. L. Potter

    (Wolfson Laboratory of Medicinal Chemistry, University of Bath)

  • Masato Hirata

    (Laboratory of Molecular and Cellular Biochemistry, Graduate School of Dental Sciences, Kyushu University and Kyushu University Station for Collaborative Research)

  • Reinhold Penner

    (Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine at The University of Hawaii)

Abstract

Receptor-mediated generation of inositol 1,4,5-trisphosphate (InsP3) initiates Ca2+ release from intracellular stores and the subsequent activation of store-operated calcium influx1. InsP3 is metabolized within seconds by 5-phosphatase and 3-kinase2, yielding Ins(1,4)P2 and inositol 1,3,4,5-tetrakisphosphate (InsP4), respectively. Some studies have suggested that InsP4 controls Ca2+ influx in combination with InsP3 (refs 3 and 4), but another study did not find the same result5. Some of the apparent conflicts between these previous studies have been resolved6; however, the physiological function of InsP4 remains elusive7,8. Here we have investigated the function of InsP4 in Ca2+ influx in the mast cell line RBL-2H3, and we show that InsP4 inhibits InsP3 metabolism through InsP3 5-phosphatase, thereby facilitating the activation of the store-operated Ca2+ current ICRAC (ref. 9). Physiologically, this mechanism opens a discriminatory time window for coincidence detection that enables selective facilitation of Ca2+ influx by appropriately timed low-level receptor stimulation. At higher concentrations, InsP4 acts as an inhibitor of InsP3 receptors, enabling InsP4 to act as a potent bi-modal regulator of cellular sensitivity to InsP3, which provides both facilitatory and inhibitory feedback on Ca2+ signalling.

Suggested Citation

  • Meredith C. Hermosura & Hiroshi Takeuchi & Andrea Fleig & Andrew M. Riley & Barry V. L. Potter & Masato Hirata & Reinhold Penner, 2000. "InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase," Nature, Nature, vol. 408(6813), pages 735-740, December.
    • Handle: RePEc:nat:nature:v:408:y:2000:i:6813:d:10.1038_35047115
    DOI: 10.1038/35047115
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