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

Meredith C. Hermosura, Hiroshi Takeuchi, Andrea Fleig, Andrew M. Riley, Barry V. L. Potter, Masato Hirata and Reinhold Penner ()
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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

Nature, 2000, vol. 408, issue 6813, 735-740

Abstract: 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.

Date: 2000
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DOI: 10.1038/35047115

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