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J. Biol. Chem., Vol. 283, Issue 23, 15946-15955, June 6, 2008

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Bax Inhibitor-1 Is a pH-dependent Regulator of Ca²⁺ Channel Activity in the Endoplasmic Reticulum^*

From the ^bDepartment of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Jeonju, Chonbuk 561-181, Republic of Korea, ^aDepartment of Dental Pharmacology and Wonkwang Biomaterial Implant Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk 570-749, Republic of Korea, ⁱClinical Trial Center for Functional Foods, Chonbuk Hospital, Jeonju, Chonbuk 561-712, Republic of Korea, ^cDepartment of Biochemistry, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea, ^dCollege of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea, ^eDepartment of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea, ^fDivision of Molecular and Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 790-784, Republic of Korea, ^gDepartment of Pharmacology, Medical Research Center (MRC), College of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea, ^hDivision of Rheumatology, Department of Internal Medicine, Catholic Research Institutes of Medical Science, School of Medicine, The Catholic University of Korea, Seoul 150-010, Republic of Korea, and ^jBurnham Institute for Medical Research, La Jolla, California 02037

In this study, Bax inhibitor-1 (BI-1) overexpression reduces the ER pool of Ca²⁺ released by thapsigargin. Cells overexpressing BI-1 also showed lower intracellular Ca²⁺ release induced by the Ca²⁺ ionophore ionomycin as well as agonists of ryanodine receptors and inositol trisphosphate receptors. In contrast, cells expressing carboxyl-terminal deleted BI-1 (C-BI-1 cells) displayed normal intracellular Ca²⁺ mobilization. Basal Ca²⁺ release rates from the ER were higher in BI-1-overexpressing cells than in control or C-BI-1 cells. We determined that the carboxyl-terminal cytosolic region of BI-1 contains a lysine-rich motif (EKDKKKEKK) resembling the pH-sensing domains of ion channels. Acidic conditions triggered more extensive Ca²⁺ release from ER microsomes from BI-1-overexpressing cells and BI-1-reconsituted liposomes. Acidic conditions also induced BI-1 protein oligomerization. Interestingly subjecting BI-1-overexpressing cells to acidic conditions induced more Bax recruitment to mitochondria, more cytochrome c release from mitochondria, and more cell death. These findings suggest that BI-1 increases Ca²⁺ leak rates from the ER through a mechanism that is dependent on pH and on the carboxyl-terminal cytosolic region of the BI-1 protein. The findings also reveal a cell death-promoting phenotype for BI-1 that is manifested under low pH conditions.

Received for publication, January 4, 2008 , and in revised form, March 17, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant AG15393 (to J. C. R.). This work was also supported by Korea Research Foundation Grants KRF-2005-070-C00095, E00021 [GenBank] , and 2005-015-E00210 and Korea Science and Engineering Foundation Grants R01-2006-000-10422-0 and R01-2007-000-20275-0. 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 Figs. S1 and S2.

¹ To whom correspondence may be addressed: Burnham Inst. for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 02037. Tel.: 858-795-5301; Fax: 858-646-3194; E-mail: jreed{at}burnham.org. ² To whom correspondence may be addressed: Dept. of Pharmacology and Inst. of Cardiovascular Research, Medical School, Chonbuk University, Jeonju, Chonbuk 561-181, Republic of Korea. Tel.: 82-63-270-3092; Fax: 82-63-275-2855; E-mail: hjchae{at}chonbuk.ac.kr.

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