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J. Biol. Chem., Vol. 280, Issue 8, 6816-6822, February 25, 2005

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Cluster Formation of Inositol 1,4,5-Trisphosphate Receptor Requires Its Transition to Open State^*

Yoko Tateishi, Mitsuharu Hattori¶, Tomohiro Nakayama, Miwako Iwai, Hiroko Bannai||, Takeshi Nakamura**, Takayuki Michikawa**, Takafumi Inoue**, and Katsuhiko Mikoshiba||**

From the Division of Molecular Neurobiology, Institute of Medical Science and Division of Neural Signal Information, NTT-IMSUT, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency (JST), 4-1-8 Hon-machi, Kawaguchi, Saitama 332-0012, ^||Developmental Brain Science Group, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, and ^**Calcium Oscillation Project, International Cooperative Research Project, JST, 3-4-4 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan

The inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R) Ca²⁺ channel plays pivotal roles in many aspects of physiological and pathological events. It was previously reported that IP₃R forms clusters on the endoplasmic reticulum when cytosolic Ca²⁺ concentration ([Ca²⁺]_C) is elevated. However, the molecular mechanism of IP₃R clustering remains largely unknown, and thus its physiological significance is far from clear. In this study we found that the time course of clustering of green fluorescent protein-tagged IP₃R type 1 (GFP-IP₃R1), evoked by IP₃-generating agonists, did not correlate with [Ca²⁺]_C but seemed compatible with cytoplasmic IP₃ concentration. IP₃ production alone induced GFP-IP₃R1 clustering in the absence of a significant increase in [Ca²⁺]_C but elevated [Ca²⁺]_C without IP₃ production did not. Moreover IP₃R1 mutants that do not undergo an IP₃-induced conformational change failed to form clusters. Thus, IP₃R clustering is induced by its IP₃-induced conformational change to the open state. We also found that GFP-IP₃R1 clusters colocalized with ERp44, a luminal protein of endoplasmic reticulum that inhibits its channel activity. This is the first example of ligand-induced clustering of a ligand-gated channel protein.

Received for publication, May 17, 2004 , and in revised form, November 4, 2004.

^* This study was supported by grants from the Ministry of Education and Science of Japan and from JST. 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Video 1.

^¶ To whom correspondence should be addressed: Division of Molecular Neurobiology, Inst. of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Tel.: 81-3-5449-5316; Fax: 81-3-5440-5420; E-mail: mhattori{at}ims.u-tokyo.ac.jp.

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