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J. Biol. Chem., Vol. 280, Issue 28, 26024-26031, July 15, 2005

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The Pro³³⁵ Leu Polymorphism of Type 3 Inositol 1,4,5-Trisphosphate Receptor Found in Mouse Inbred Lines Results in Functional Change^*

Sanghyeon Kim, Taeho Ahn¶, and Chankyu Park||

From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Yusong-gu, Daejeon and the Department of Biochemistry, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea

Inositol 1,4,5-trisphosphate receptor (IP₃R) is an intracellular Ca²⁺ channel involved in various cellular signaling. Type 3 IP₃R (IP₃R3) retains ligand-gated Ca²⁺ channel properties differing from other subtypes in terms of IP₃-binding affinity and regulation of its channel activity by effector molecules. In this study, we found the natural Pro³³⁵ Leu polymorphism of mouse IP₃R3 between BALB/c and C57BL/6J. We investigated the functional differences between Pro³³⁵IP₃R3 and Leu³³⁵IP₃R3 with purified receptors reconstituted into proteoliposomes as well as with soluble ligand binding domains. Pro³³⁵IP₃R3 exhibited significantly higher IP₃-binding affinity and IP₃-induced Ca²⁺ release than those of Leu³³⁵IP₃R3 in both forms of the receptor. Moreover, the polymorphic change caused differences in the effect of external Ca²⁺ on IP₃-induced Ca²⁺ release. The Pro³³⁵ Leu substitution alters the conformation of soluble ligand binding domain as revealed by intrinsic fluorescence and circular dichroism spectra with or without Ca²⁺. The results indicate that the polymorphism of IP₃R3 causes changes in receptor function, presumably affecting intracellular Ca²⁺ signaling.

Received for publication, February 16, 2005 , and in revised form, May 4, 2005.

^* This work was supported in part by the Glycomics Program and Grant BK21 (to C. P.) from the Ministry of Education, Korea. 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.

^¶ To whom correspondence may be addressed: Dept. of Biochemistry, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea. E-mail: thahn{at}chonnam.ac.kr. || To whom correspondence may be addressed: Dept. of Life Sciences, Korea Advanced Institute of Science and Technology, Yusong-gu, Daejeon 305-701, Korea. Tel.: 82-42-869-2629; Fax: 82-42-869-2629; E-mail: ckpark{at}kaist.ac.kr.

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