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J. Biol. Chem., Vol. 280, Issue 5, 3824-3831, February 4, 2005

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Translational Mobility of the Type 3 Inositol 1,4,5-Trisphosphate Receptor Ca²⁺ Release Channel in Endoplasmic Reticulum Membrane^*

Michelle Ferreri-Jacobia, Don-On Daniel Mak, and J. Kevin Foskett

From the Department of Physiology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104

The inositol 1,4,5-trisphosphate receptor (InsP₃R) is an integral membrane protein in the endoplasmic reticulum (ER) which functions as a ligand-gated Ca²⁺ release channel. InsP₃-mediated Ca²⁺ release modulates the cytoplasmic free Ca²⁺ concentration ([Ca²⁺]_i), providing a ubiquitous intracellular signal with high temporal and spatial specificity. Precise localization of the InsP₃R is believed to be important for providing local [Ca²⁺] regulation and for ensuring efficient functional coupling between Ca²⁺ release sites by enabling graded recruitment of channels with increasing stimulus strength in the face of the intrinsically unstable regenerative process of Ca²⁺-induced Ca²⁺ release. Highly localized Ca²⁺ release has been attributed to the ability of the InsP₃R channels to cluster and to be localized to discrete areas, suggesting that mechanisms may exist to restrict their movement. Here, we examined the lateral mobility of the type 3 isoform of the InsP₃R (InsP₃R3) in the ER membrane by performing confocal fluorescence recovery after photobleaching of an InsP₃R3 with green fluorescent protein fused to its N terminus. In Chinese hamster ovary and COS-7 cells, the diffusion coefficient D was 4 x 10^-10 cm²/s at room temperature, a value similar to that determined for other ER-localized integral membrane proteins, with a high fraction (75%) of channels mobile. D was modestly increased at 37 °C, and it as well as the mobile fraction were reversibly reduced by ATP depletion. Although disruption of the actin cytoskeleton (latrunculin) was without effect, disruption of microtubules (nocodazole) reduced D by half without affecting the mobile fraction. We conclude that the entire ER is continuous in these cells, with the large majority of InsP₃R3 channels free to diffuse throughout it, at rates that are comparable with those measured for other polytopic ER integral membrane proteins. The observed InsP₃R3 mobility may be higher than its intrinsic diffusional mobility because of additional ATP- and microtubule-facilitated motility of the channel.

Received for publication, August 17, 2004 , and in revised form, November 5, 2004.

^* This work was supported by National Institutes of Health Grant MH59937 (to J. K. F.) and by National Institutes of Health Training Grant T32-HL007027. 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 should be addressed: Dept. of Physiology, B-39 Anatomy-Chemistry Bldg., University of Pennsylvania, Philadelphia, PA 19104-6085. Tel.: 215-898-1354; Fax: 215-573-6808; E-mail: foskett{at}mail.med.upenn.edu.

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