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, Reinhold Penner

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)735-740
Number of pages6
JournalNature
Volume408
Issue number6813
DOIs
Publication statusPublished - Dec 7 2000

All Science Journal Classification (ASJC) codes

  • General

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