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J Biol Chem, Vol. 274, Issue 6, 3476-3484, February 5, 1999

Inositol 1,4,5-Trisphosphate Receptor Down-regulation Is Activated Directly by Inositol 1,4,5-Trisphosphate Binding
STUDIES WITH BINDING-DEFECTIVE MUTANT RECEPTORS

Chang-Cheng Zhu, Teiichi Furuichi^§, Katsuhiko Mikoshiba^§, and Richard J. H. Wojcikiewicz

From the  Department of Pharmacology, College of Medicine, State University of New York Health Science Center at Syracuse, New York 13210-2339 and the ^§ Department of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan

Activation of certain phosphoinositidase C-linked cell surface receptors is known to cause an acceleration of the proteolysis of inositol 1,4,5-trisphosphate (InsP₃) receptors and, thus, lead to InsP₃ receptor down-regulation. To gain insight into this process, we examined whether or not InsP₃ receptor degradation is a direct consequence of InsP₃ binding by analyzing the down-regulation of exogenous wild-type and binding-defective mutant InsP₃ receptors expressed in SH-SY5Y human neuroblastoma cells. Stimulation of these cells with carbachol showed that wild-type exogenous receptors could be down-regulated but that the binding-defective mutant exogenous receptors were not. Thus, InsP₃ binding appears to mediate down-regulation. To validate this conclusion, a comprehensive analysis of the effects of the exogenous receptors was undertaken. This showed that exogenous receptors (i) are localized appropriately within the cell, (ii) enhance InsP₃-induced Ca²⁺ release in permeabilized cells, presumably by increasing the number of InsP₃-sensitive Ca²⁺ channels, (iii) have minimal effects on Ca²⁺ mobilization and InsP₃ formation in intact cells, (iv) form heteromers with endogenous receptors, and (v) do not alter the down-regulation of endogenous receptors. In total, these data show that the introduction of exogenous receptors into SH-SY5Y cells does not compromise intracellular signaling or the down-regulatory process. We can thus conclude that InsP₃ binding directly activates InsP₃ receptor degradation. Because InsP₃ binding induces a conformational change in the InsP₃ receptor, these data suggest that this change provides the signal for accelerated proteolysis.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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