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Volume 271, Number 28, Issue of July 12, 1996 pp. 16652-16655
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Degradation of Inositol 1,4,5-Trisphosphate Receptors during Cell Stimulation Is a Specific Process Mediated by Cysteine Protease Activity

(Received for publication, March 18, 1996)

From the Department of Pharmacology, College of Medicine, SUNY Health Science Center at Syracuse, Syracuse, New York 13210-2339

Inositol 1,4,5-trisphosphate (InsP₃) receptors are down-regulated in response to chronic activation of certain cell surface receptors because their degradation is accelerated. Studies on the nature of the down-regulatory process and the protease(s) responsible for receptor degradation are described here. InsP₃ receptor down-regulation was not accompanied by parallel changes in the concentrations of several other relevant proteins (endoplasmic reticulum Ca²⁺-ATPase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and protein kinases  and ). Thus, the down-regulatory process selectively targets InsP₃ receptors for degradation. Furthermore, down-regulation was unaffected by brefeldin A and NH₄Cl, indicating that InsP₃ receptor degradation occurs without removal of receptors from the endoplasmic reticulum and independently of functional lysosomes. Analysis of InsP₃ receptor immunofluorescence confirmed that the receptors are not redistributed prior to or during down-regulation. Finally, of a range of protease inhibitors tested, only N-acetyl-Leu-Leu-norleucinal blocked down-regulation. Thus, cysteine protease activity accounts for InsP₃ receptor degradation and analysis of proteolysis in permeabilized cells indicates that this activity is calpain. Thus, InsP₃ receptor down-regulation appears to result from the highly selective calpain-mediated degradation of InsP₃ receptors. Calpain activity may be stimulated by the high concentrations of Ca²⁺ that are thought to be found in the vicinity of activated InsP₃ receptors.

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