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J. Biol. Chem., Vol. 279, Issue 42, 43378-43381, October 15, 2004

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Signaling by Higher Inositol Polyphosphates

SYNTHESIS OF BISDIPHOSPHOINOSITOL TETRAKISPHOSPHATE ("InsP₈") IS SELECTIVELY ACTIVATED BY HYPEROSMOTIC STRESS^*

Xavier Pesesse, Kuicheon Choi, Tong Zhang, and Stephen B. Shears

From the Inositide Signaling Group, NIEHS, National Institutes of Health, Department of Health and Social Services, Research Triangle Park, North Carolina 27709

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 p38MAP/ 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.

Received for publication, June 18, 2004 , and in revised form, August 4, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures.

To whom correspondence should be addressed: Inositide Signaling Group, NIEHS, NIH, DHSS, P. O. Box 12233, Research Triangle Park, NC 27709. Tel.: 919-541-0793; Fax: 919-541-0559; E-mail: shears{at}niehs.nih.gov.

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