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J. Biol. Chem., Vol. 279, Issue 34, 35551-35556, August 20, 2004

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Functional Coupling of Chromogranin with the Inositol 1,4,5-Trisphosphate Receptor Shapes Calcium Signaling^*

Chi-Un Choe, Kenneth D. Harrison, Wayne Grant, and Barbara E. Ehrlich¶

From the Department of Pharmacology and Cellular & Molecular Physiology, Yale University, New Haven, Connecticut 06520 and Institute for Neural Signal Transduction, Zentrum fuer Molekulare Neurobiologie Hamburg, University of Hamburg, 20251 Hamburg, Germany

Chromogranins A and B are high capacity, low affinity calcium (Ca²⁺) storage proteins that bind to the inositol 1,4,5-trisphosphate-gated receptor (InsP₃ R). Although most commonly associated with secretory granules of neuroendocrine cells, chromogranins have also been found in the lumen of the endoplasmic reticulum (ER) of many cell types. To investigate the functional consequences of the interaction between the InsP₃ R and the chromogranins, we disrupted the interaction between the two proteins by adding a chromogranin fragment, which competed with chromogranin for its binding site on the InsP₃R. Responses were monitored at the single channel level and in intact cells. When using InsP₃ R type I incorporated into planar lipid bilayers and activated by cytoplasmic InsP₃ and luminal chromogranin, the addition of the fragment reversed the enhancing effect of chromogranin. Moreover, the expression of the fragment in the ER of neuronally differentiated PC12 cells attenuated agonist-induced intracellular Ca²⁺ signaling. These results show that the InsP₃R/chromogranin interaction amplifies Ca²⁺ release from the ER and that chromogranin is an essential component of this intracellular channel complex.

Received for publication, October 13, 2003 , and in revised form, June 8, 2004.

^* This work was supported by Grant GM63496 from the National Institutes of Health and a German National Merit Foundation scholarship (to C. C.). 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 Pharmacology, 333 Cedar St., Yale University, New Haven, CT 06520-8066. Tel.: 203-737-1158; Fax: 203-785-7670; E-mail: barbara.ehrlich{at}yale.edu .

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