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

Receptor-mediated generation of inositol 1,4,5-trisphosphate (InsP(3)) initiates Ca2+ release from intracellular stores and the subsequent activation of store-operated calcium influx(1). InsP(3) is metabolized within seconds by 5-phosphatase and 3-kinase(2), yielding Ins(1,4)P-2 and inositol 1,3,4,5-tetrakisphosphate (InsP(4)), respectively. Some studies have suggested that InsP(4) controls Ca2+ influx in combination with InsP(3) (refs 3 and 4), but another study did not find the same result(5). Some of the apparent conflicts between these previous studies have been resolved(6); however, the physiological function of InsP(4) remains elusive(7,8). Here we have investigated the function of InsP(4) in Ca2+ influx in the mast cell line RBL-2H3, and we show that InsP(4) inhibits InsP(3) metabolism through InsP(3) 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, InsP(4) acts as an inhibitor of InsP(3) receptors, enabling InsP(4) to act as a potent bi-modal regulator of cellular sensitivity to InsP(3), which provides both facilitatory and inhibitory feedback on Ca2+ signalling.