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J. Biol. Chem., Vol. 283, Issue 5, 2939-2948, February 1, 2008

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Molecular Characterization of the Inositol 1,4,5-Trisphosphate Receptor Pore-forming Segment^*

Zachary T. Schug, Paula C. A. da Fonseca, Cunnigaiper D. Bhanumathy, Larry Wagner, II^¶, Xianchao Zhang¹, Bradley Bailey, Edward P. Morris, David I. Yule^¶, and Suresh K. Joseph²

From the Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, the Institute for Cancer Research, Chester Beatty Laboratories, London SW3 6JB, United Kingdom, and the ^¶Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642

Specific residues in the putative pore helix, selectivity filter, and S6 transmembrane helix of the inositol 1,4,5-trisphosphate receptor were mutated in order to examine their effects on channel function. Mutation of 5 of 8 highly conserved residues in the pore helix/selectivity filter region inactivated the channel (C2533A, G2541A, G2545A, G2546A, and G2547A). Of the remaining three mutants, C2527A and R2543A were partially active and G2549A behaved like wild type receptor. Mutation of a putative glycine hinge residue in the S6 helix (G2586A) or a putative gating residue at the cytosolic end of S6 helix (F2592A) had minimal effects on function, although channel function was inactivated by G2586P and F2592D mutations. The mutagenesis data are interpreted in the context of a structural homology model of the inositol 1,4,5-trisphosphate receptor.

Received for publication, August 10, 2007 , and in revised form, October 9, 2007.

^* This work was supported by National Institutes of Health Grants DK34804 (to S. K. J.), DK54568 (to D. I. Y.), and DE14756 (to D. I. Y.) and Training Grant T32-AA07463 (to Z. T. S.) and by the Wellcome Trust (to P. C. A. d. F. and E. P. M.). 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 Present address: Drexel Institute for Biotechnology and Virology Research, Doylestown, PA 18902.

² To whom correspondence should be addressed: Dept. of Pathology and Cell Biology, Thomas Jefferson University, 1020 Locust St. JAH 230A, Philadelphia, PA 19107. Tel.: 215-503-1222; Fax: 215-923-6813; E-mail: suresh.joseph{at}jefferson.edu.

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