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J. Biol. Chem., Vol. 283, Issue 31, 21579-21587, August 1, 2008

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ATP Modulation of Ca²⁺ Release by Type-2 and Type-3 Inositol (1, 4, 5)-Triphosphate Receptors

DIFFERING ATP SENSITIVITIES AND MOLECULAR DETERMINANTS OF ACTION^*

Matthew J. Betzenhauser¹, Larry E. Wagner, II, Miwako Iwai, Takayuki Michikawa^¶, Katsuhiko Mikoshiba^¶, and David I. Yule²

From the Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, the Division of Molecular Neurobiology, Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Tokyo, Japan, and the ^¶Laboratory for Developmental Neurobiology, Brain Development Research Group, Brain Science Institute, RIKEN, Saitama, Japan

ATP enhances Ca²⁺ release from inositol (1,4,5)-trisphosphate receptors (InsP₃R). However, the three isoforms of InsP₃R are reported to respond to ATP with differing sensitivities. Ca²⁺ release through InsP₃R1 is positively regulated at lower ATP concentrations than InsP₃R3, and InsP₃R2 has been reported to be insensitive to ATP modulation. We have reexamined these differences by studying the effects of ATP on InsP₃R2 and InsP₃R3 expressed in isolation on a null background in DT40 InsP₃R knockout cells. We report that the Ca²⁺-releasing activity as well as the single channel open probability of InsP₃R2 was enhanced by ATP, but only at submaximal InsP₃ levels. Further, InsP₃R2 was more sensitive to ATP modulation than InsP₃R3 under similar experimental conditions. Mutations in the ATPB sites of InsP₃R2 and InsP₃R3 were generated, and the functional consequences of these mutations were tested. Surprisingly, mutation of the ATPB site in InsP₃R3 had no effect on ATP modulation, suggesting an additional locus for the effects of ATP on this isoform. In contrast, ablation of the ATPB site of InsP₃R2 eliminated the enhancing effects of ATP. Furthermore, this mutation had profound effects on the patterns of intracellular calcium signals, providing evidence for the physiological significance of ATP binding to InsP₃R2.

Received for publication, February 29, 2008 , and in revised form, April 18, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants RO1-DK054568 and RO1-DE016999 (to D. I. Y.). 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.

¹ Supported by NIDCR, National Institutes of Health, Training Grant T32-DE07202.

² To whom correspondence should be addressed: 601 Elmwood Ave., Box 711, Rochester, NY 14625. Tel.: 585-273-2154; Fax: 585-273-2652; E-mail: David_Yule{at}urmc.rochester.edu.

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