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J. Biol. Chem., Vol. 281, Issue 19, 13057-13067, May 12, 2006

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Critical Role of Phospholipase C1 in the Generation of H₂O₂-evoked [Ca²⁺]_i Oscillations in Cultured Rat Cortical Astrocytes^*

Jeong Hee Hong, Seok Jun Moon¹, Hae Mi Byun, Min Seuk Kim, Hae Jo, Yun Soo Bae, Syng-Ill Lee, Martin D. Bootman^¶2, H. Llewelyn Roderick^¶||3, Dong Min Shin⁴, and Jeong Taeg Seo⁵

From the Department of Oral Biology, Brain Korea 21 Project for Medical Science, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, 120-752, Korea, Division of Molecular Life Science, Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, Korea, ^¶Laboratory of Molecular Signalling, The Babraham Institute, Babraham, CB2 4AT Cambridge, United Kingdom, and the ^||Department of Pharmacology, University of Cambridge, CB2 1PD Cambridge, United Kingdom

Reactive oxygen species, such as the superoxide anion, H₂O₂, and the hydroxyl radical, have been considered as cytotoxic by-products of cellular metabolism. However, recent studies have provided evidence that H₂O₂ serves as a signaling molecule modulating various physiological functions. Here we investigated the effect of H₂O₂ on the regulation of intracellular Ca²⁺ signaling in rat cortical astrocytes. H₂O₂ triggered the generation of oscillations of intracellular Ca²⁺ concentration ([Ca²⁺]_i) in a concentration-dependent manner over the range 10–100µM. The H₂O₂-induced [Ca²⁺]_i oscillations persisted in the absence of extracellular Ca²⁺ and were prevented by depletion of intracellular Ca²⁺ stores with thapsigargin. The H₂O₂-induced [Ca²⁺]_i oscillations were not inhibited by pretreatment with ryanodine but were prevented by 2-aminoethoxydiphenyl borate and caffeine, known antagonists of inositol 1,4,5-trisphosphate receptors. H₂O₂ activated phospholipase C (PLC) 1 in a dose-dependent manner, and U73122 [GenBank] , an inhibitor of PLC, completely abolished the H₂O₂-induced [Ca²⁺]_i oscillations. In addition, RNA interference against PLC1 and the expression of the inositol 1,4,5-trisphosphate-sequestering "sponge" prevented the generation of [Ca²⁺]_i oscillations. H₂O₂-induced [Ca²⁺]_i oscillations and PLC1 phosphorylation were inhibited by pretreatment with dithiothreitol, a sulfhydryl-reducing agent. Finally, epidermal growth factor induced H₂O₂ production, PLC1 activation, and [Ca²⁺]_i increases, which were attenuated by N-acetylcysteine and diphenyleneiodonium and by the overexpression of peroxiredoxin type II. Therefore, we conclude that low concentrations of exogenously applied H₂O₂ generate [Ca²⁺]_i oscillations by activating PLC1 through sulfhydryl oxidation-dependent mechanisms. Furthermore, we show that this mechanism underlies the modulatory effect of endogenously produced H₂O₂ on epidermal growth factor-induced Ca²⁺ signaling in rat cortical astrocytes.

Received for publication, February 23, 2006

^* This work was supported in part by Korea Health 21 R & D Project, the Ministry of Health & Welfare, and Republic of Korea Grants 03-PJ1-PG3-21400-0005, 02-PJ1-PG3-20706-0001, and A050002. 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 Fig. S1.

¹ Present address: Dept. of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196.

² Recipient of support from the Biotechnology and Biological Sciences Research Council.

³ Recipient of a Royal Society for Research fellowship.

⁴ To whom correspondence may be addressed. Tel.: 82-2-2228-3051; Fax: 82-2-364-1085; E-mail: dmshin{at}yumc.yonsei.ac.kr. ⁵ To whom correspondence may be addressed: Tel.: 82-2-2228-3054; Fax: 82-2-364-1085; E-mail: jeong{at}yumc.yonsei.ac.kr.

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