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J. Biol. Chem. 275 (9): 6063-6066

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

J Biol Chem, Vol. 275, Issue 9, 6063-6066, March 3, 2000

Inositol Tetrakisphosphate as a Frequency Regulator in Calcium Oscillations in HeLa Cells*

De-Min ZhuDagger , Ephrem Tekle, Charles Y. Huang, and P. Boon Chock§

From the Laboratory of Biochemistry, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

Cellular signaling mediated by inositol (1,4,5)trisphosphate (Ins(1,4,5)P3) results in oscillatory intracellular calcium (Ca2+) release. Because the amplitude of the Ca2+ spikes is relatively invariant, the extent of the agonist-mediated effects must reside in their ability to regulate the oscillating frequency. Using electroporation techniques, we show that Ins(1,4,5)P3, Ins(1,3,4,5)P4, and Ins(1,3,4,6)P4 cause a rapid intracellular Ca2+ release in resting HeLa cells and a transient increase in the frequency of ongoing Ca2+ oscillations stimulated by histamine. Two poorly metabolizable analogs of Ins(1,4,5)P3, Ins(2,4,5)P3, and 2,3-dideoxy-Ins(1,4,5)P3, gave a single Ca2+ spike and failed to alter the frequency of ongoing oscillations. Complete inhibition of Ins(1,4,5)P3 3-kinase (IP3K) by either adriamycin or its specific antibody blocked Ca2+ oscillations. Partial inhibition of IP3K causes a significant reduction in frequency. Taken together, our results indicate that Ins(1,3,4,5)P4 is the frequency regulator in vivo, and IP3K, which phosphorylates Ins(1,4,5)P3 to Ins(1,3,4,5)P4, plays a major regulatory role in intracellular Ca2+ oscillations.

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

Dagger Present address: Immunology Dept., Wayne Hughes Institute, 2665 Long Lake Rd., St. Paul, MN 55113.

§ To whom correspondence should be addressed: Laboratory of Biochemistry, NHLBI, National Institutes of Health, Bldg. 3, Rm. 204, 3 Center Dr., MSC-0342, Bethesda, MD 20892-0342. Tel.: 301-496-2073; Fax: 301-496-0599. E-mail:

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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