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J. Biol. Chem., Vol. 278, Issue 47, 46210-46218, November 21, 2003

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Cytosolic Multiple Inositol Polyphosphate Phosphatase in the Regulation of Cytoplasmic Free Ca²⁺ Concentration^*

Jia Yu, Barbara Leibiger, Shao-Nian Yang, James J. Caffery¶, Stephen B. Shears¶, Ingo B. Leibiger, Christopher J. Barker||, and Per-Olof Berggren

From the Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, L3, Karolinska Institutet, Karolinska Hospital, Stockholm SE-171 76, Sweden and ^¶Inositide Signaling Section, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Multiple inositol polyphosphate phosphatase (MIPP) is an enzyme that, in vitro, has the interesting property of degrading higher inositol polyphosphates to the Ca²⁺ second messenger, inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃), independently of inositol lipid breakdown. We hypothesized that a truncated cytosolic form of the largely endoplasmic reticulum-confined MIPP (cyt-MIPP) could representanimportantnewtoolintheinvestigationofIns(1,4,5)P₃-dependent intracellular Ca²⁺ homeostasis. To optimize our ability to judge the impact of cyt-MIPP on intracellular Ca²⁺ concentration ([Ca²⁺]_i) we chose a poorly responsive -cell line (HIT M2.2.2) with an abnormally low [Ca²⁺]_i. Our results show for the first time in an intact mammalian cell that cyt-MIPP expression leads to a significant enhancement of Ins(1,4,5)P₃ concentration. This is achieved without a significant interference from other cyt-MIPP-derived inositol phosphates. Furthermore, the low basal [Ca²⁺]_i of these cells was raised to normal levels (35 to 115 nM) when they expressed cyt-MIPP. Noteworthy is that the normal feeble glucose-induced Ca²⁺ response of HIT M2.2.2 cells was enhanced dramatically by mechanisms related to this increase in basal [Ca²⁺]_i. These data support the use of cyt-MIPP as an important tool in investigating Ins(1,4,5)P₃-dependent Ca²⁺ homeostasis and suggest a close link between Ins(1,4,5)P₃ concentration and basal [Ca²⁺]_i, the latter being an important modulator of Ca²⁺ signaling in the pancreatic -cell.

Received for publication, April 10, 2003 , and in revised form, September 5, 2003.

^* This work was supported by grants from Karolinska Institutet, Novo Nordisk Foundation, the National Institutes of Health (DK-58508), the Swedish Research Council, the Swedish Diabetes Association, Juvenile Diabetes Research Foundation International, Åke Wibergs Foundation, and Berth von Kantzow's Foundation. 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.

Contributed equally to this work

^|| To whom correspondence should be addressed. Tel.: 46-8-517-79454; Fax: 46-8-517-79450; E-mail: chris.barker{at}molmed.ki.se.

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