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 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 elusive^7,8. 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 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.