title: InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase.
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 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.
authors.affiliation: Laboratory of Cell and Molecular Signaling, Center for Biomedical Research and John A Burns School of Medicine at The University of Hawaii, Honolulu 96813, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Hermosura
authors.forename: H
authors.initials: H
authors.lastname: Takeuchi
authors.forename: A
authors.initials: A
authors.lastname: Fleig
authors.forename: A M
authors.initials: AM
authors.lastname: Riley
authors.forename: B V
authors.initials: BV
authors.lastname: Potter
authors.forename: M
authors.initials: M
authors.lastname: Hirata
authors.forename: R
authors.initials: R
authors.lastname: Penner
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D007295:Inositol Phosphates / Q000378:metabolism*; D000072181:Inositol Polyphosphate 5-Phosphatases; D008407:Mast Cells / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; C061107:inositol-1,3,4,5-tetrakisphosphate receptor; C081655:inositol-1,3,4,5-tetrakisphosphate; D004317:Doxorubicin; C062616:inositol 2,4,5-trisphosphate; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D002118:Calcium