Signaling by higher inositol polyphosphates. Synthesis of bisdiphosphoinositol tetrakisphosphate ("InsP8") is selectively activated by hyperosmotic stress.

Evidence has accumulated that inositol pyrophosphates (diphosphoinositol pentakisphosphate (PP-InsP5) and bisdiphosphoinositol tetrakisphosphate ([PP]2-InsP4)) are intracellular signals that regulate many cellular processes including endocytosis, vesicle trafficking, apoptosis, and DNA repair. Yet, in contrast to the situation with all other second messengers, no one studying multicellular organisms has previously described a stimulus that acutely and specifically elevates cellular levels of PP-InsP5 or [PP]2-InsP4. We now show up to 25-fold elevations in [PP]2-InsP4 levels in animal cells. Importantly, this does not involve classical agonists. Instead, we show that this [PP]2-InsP4 response is a novel consequence of the activation of ERK1/2 and p38MAPalpha/beta kinases by hyperosmotic stress. JNK did not participate in regulating [PP]2-InsP4 levels. Identification of [PP]2-InsP4 as a sensor of hyperosmotic stress opens up a new area of research for studies into the cellular activities of higher inositol phosphates.