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

Nature. 2000 Dec 7;408(6813):735-40. doi: 10.1038/35047115.


Receptor-mediated generation of inositol 1,4,5-trisphosphate (InsP3) initiates Ca2+ release from intracellular stores and the subsequent activation of store-operated calcium influx. InsP3 is metabolized within seconds by 5-phosphatase and 3-kinase, 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 result. Some of the apparent conflicts between these previous studies have been resolved; however, the physiological function of InsP4 remains elusive. 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 I(CRAC) (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Signaling
  • Cell Line
  • Doxorubicin / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli
  • Inositol Phosphates / metabolism*
  • Inositol Polyphosphate 5-Phosphatases
  • Mast Cells / metabolism*
  • Patch-Clamp Techniques
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / metabolism
  • Rats
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • Enzyme Inhibitors
  • Inositol Phosphates
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Proteins
  • inositol-1,3,4,5-tetrakisphosphate receptor
  • inositol-1,3,4,5-tetrakisphosphate
  • Doxorubicin
  • inositol 2,4,5-trisphosphate
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • Calcium