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Volume 272, Number 15, Issue of April 11, 1997 pp. 9956-9961
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Adenophostin A Can Stimulate Ca²⁺ Influx without Depleting the Inositol 1,4,5-Trisphosphate-sensitive Ca²⁺ Stores in the Xenopus Oocyte

(Received for publication, December 2, 1996, and in revised form, February 3, 1997)

Sylvain DeLisle , Erik W. Marksberry , Carl Bonnett , David J. Jenkins ^¶ , Barry V. L. Potter ^¶ , Masaaki Takahashi ^** and Kazuhiko Tanzawa ^**

From the  Veterans Administration Medical Center, Department of Internal Medicine, and Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, Iowa 52240, the ^¶ School of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom, and ^** Biological Research Laboratories, Sankyo Co. Ltd., Tokyo 108, Japan

Adenophostin A possesses the highest known affinity for the inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃) receptor (InsP₃R). The compound shares with Ins(1,4,5)P₃ those structural elements essential for binding to the InsP₃R. However, its adenosine 2-phosphate moiety has no counterpart in the Ins(1,4,5)P₃ molecule. To determine whether its unique structure conferred a distinctive biological activity, we characterized the adenophostin-induced Ca²⁺ signal in Xenopus oocytes using the Ca²⁺-gated Cl current assay. In high concentrations, adenophostin A released Ca²⁺ from Ins(1,4,5)P₃-sensitive stores and stimulated a Cl current that depended upon the presence of extracellular Ca²⁺. We used this Cl current as a marker of Ca²⁺ influx. In low concentrations, however, adenophostin A stimulated Ca²⁺ influx exclusively. In contrast, Ins(1,4,5)P₃ and (2-hydroxyethyl)--D-glucopyranoside 2,3,4-trisphosphate, an adenophostin A mimic lacking most of the adenosine moiety, always released intracellular Ca²⁺ before causing Ca²⁺ influx. Ins(1,4,5)P₃ could still release Ca²⁺ during adenophostin A-induced Ca²⁺ influx, confirming that the Ins(1,4,5)P₃-sensitive intracellular Ca²⁺ stores had not been emptied. Adenophostin- and Ins(1,4,5)P₃-induced Ca²⁺ influx were not additive, suggesting that both agonists stimulated a common Ca²⁺ entry pathway. Heparin, which blocks binding to the InsP₃R, prevented adenophostin-induced Ca²⁺ influx. These data indicate that adenophostin A can stimulate the influx of Ca²⁺ across the plasma membrane without inevitably emptying the Ins(1,4,5)P₃-sensitive intracellular Ca²⁺ stores.

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