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J. Biol. Chem., Vol. 283, Issue 38, 26081-26088, September 19, 2008

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The Type 2 Inositol (1,4,5)-Trisphosphate (InsP₃) Receptor Determines the Sensitivity of InsP₃-induced Ca²⁺ Release to ATP in Pancreatic Acinar Cells^*

Hyung Seo Park¹, Matthew J. Betzenhauser¹², Jong Hak Won, Ju Chen^¶, and David I. Yule

From the Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York 14642, the Department of Physiology, College of Medicine, Konyang University, Daejeon 302-718, South Korea, and the ^¶Department of Medicine, University of California San Diego, La Jolla, California 92093

Calcium release through inositol (1,4,5)-trisphosphate receptors (InsP₃R) is the primary signal driving digestive enzyme and fluid secretion from pancreatic acinar cells. The type 2 (InsP₃R2) and type 3 (InsP₃R3) InsP₃R are the predominant isoforms expressed in acinar cells and are required for proper exocrine gland function. Both InsP₃R2 and InsP₃R3 are positively regulated by cytosolic ATP, but InsP₃R2 is 10-fold more sensitive than InsP₃R3 to this form of modulation. In this study, we examined the role of InsP₃R2 in setting the sensitivity of InsP₃-induced Ca²⁺ release (IICR) to ATP in pancreatic acinar cells. IICR was measured in permeabilized acinar cells from wild-type (WT) and InsP₃R2 knock-out (KO) mice. ATP augmented IICR from WT pancreatic cells with an EC₅₀ of 38 µM. However, the EC₅₀ was 10-fold higher in acinar cells isolated from InsP₃R2-KO mice, indicating a role for InsP₃R2 in setting the sensitivity of IICR to ATP. Consistent with this idea, heterologous expression of InsP₃R2 in RinM5F cells, which natively express predominately InsP₃R3, increased the sensitivity of IICR to ATP. Depletion of ATP attenuated agonist-induced Ca²⁺ signaling in WT pancreatic acinar cells. This effect was more profound in acinar cells prepared from InsP₃R2-KO mice. These data suggest that the sensitivity of IICR to ATP depletion is regulated by the particular complement of InsP₃R expressed in an individual cell. The effects of metabolic stress on intracellular Ca²⁺ signals can therefore be determined by the relative amount of InsP₃R2 expressed in cells.

Received for publication, May 30, 2008 , and in revised form, July 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Training Grant T32-DE07202 from NIDCR (to M. J. B.), National Institutes of Health Grants RO1-DK054568 and RO1-DE016999 (to D. I. Y.), and a National Institutes of Health grant (to J. C). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Ave., Box 711, Rochester, NY 14642. Tel.: 585-273-2154; Fax: 585-273-2652; E-mail: Matthew_Betzenhauser{at}urmc.rochester.edu.

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