HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 17, 11477-11484, April 25, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/17/11477    most recent M708385200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xu, C. Articles by Reed, J. C. Search for Related Content PubMed PubMed Citation Articles by Xu, C. Articles by Reed, J. C. Social Bookmarking                      What's this?

BI-1 Regulates Endoplasmic Reticulum Ca²⁺ Homeostasis Downstream of Bcl-2 Family Proteins^*

Chunyan Xu¹, Wenjie Xu¹, Amy E. Palmer², and John C. Reed³

From the Program on Apoptosis and Cell Death Research, Burnham Institute for Medical Research, La Jolla, California 92037 and the Department of Pharmacology, University of California, San Diego, La Jolla, California 92093

BI-1 (Bax inhibitor-1) is an evolutionarily conserved multitransmembrane protein that resides in the endoplasmic reticulum (ER) and that has documented cytoprotective functions in both animals and plants. Recent studies indicate that BI-1 shares in common with Bcl-2/Bax family proteins the ability to regulate the amounts of Ca²⁺ that can be released from the ER by agents, such as the ER-Ca²⁺-ATPase (SERCA) inhibitor thapsigargin (TG). Using an ER-targeted, Ca²⁺ indicator (cameleon), with characteristics optimized for measuring ER Ca²⁺ ([Ca²⁺]_er), we studied the effects of BI-1 on [Ca²⁺]_er in resting and TG-treated cells. Similar to cells overexpressing antiapoptotic Bcl-2 or Bcl-X_L, overexpression of BI-1 resulted in lower resting [Ca²⁺]_er, with concomitantly less Ca²⁺ released into the cytosol upon stimulation by TG and with a higher rate of Ca²⁺ leakage from the ER. Co-expression of SERCA restored levels of [Ca²⁺]_er to normal, showing opposing actions of the ER-Ca²⁺ATPase and BI-1 on ER Ca²⁺ homeostasis. Conversely, cells with deficient BI-1 have increased [Ca²⁺]_er, and release more Ca²⁺ into the cytosol when challenged with TG. In BI-1-deficient cells, Bcl-X_L fails to reduce [Ca²⁺]_er, indicating that BI-1 functions downstream of Bcl-X_L. In bax^-/-bak^-/- double knock-out cells, both BI-1 and Bcl-X_L retained their ability to reduce [Ca²⁺]_er, suggesting that BI-1 and Bcl-X_L operate downstream of or parallel to Bax/Bak. The findings reveal a hierarchy of functional interactions of BI-1 with Bcl-2/Bax family proteins in regulating ER Ca²⁺ homeostasis.

Received for publication, October 9, 2007 , and in revised form, February 25, 2008.

^* This work was supported by National Institutes of Health Grants F32-NS047855, F32-GM067488, AG15393, and NS27177 and Department of Energy Grant DE-FG-01-ER63276. 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-S4.

¹ Both authors contributed equally to this work.

² Present address: University of Colorado, Boulder, CO 80309.

³ To whom correspondence should be addressed: Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3140; Fax: 858-646-3194; E-mail: reedoffice{at}burnham.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Ahmad, A. Ahmad, E. S. Dremina, V. S. Sharov, X. Guo, T. N. Jones, J. E. Loader, J. R. Tatreau, A.-L. Perraud, C. Schoneich, et al. Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase Expression in Cystic Fibrosis Airways: Role in Oxidant-mediated Cell Death Am. J. Respir. Crit. Care Med., May 1, 2009; 179(9): 816 - 826. [Abstract] [Full Text] [PDF]

				E. Szegezdi, D. C. MacDonald, T. Ni Chonghaile, S. Gupta, and A. Samali Bcl-2 family on guard at the ER Am J Physiol Cell Physiol, May 1, 2009; 296(5): C941 - C953. [Abstract] [Full Text] [PDF]

				C. C. Chua, J. Gao, Y.-S. Ho, X. Xu, I-C. Kuo, K.-Y. Chua, H. Wang, R. C. Hamdy, J. C. Reed, and B. H.L. Chua Over-expression of a modified bifunctional apoptosis regulator protects against cardiac injury and doxorubicin-induced cardiotoxicity in transgenic mice Cardiovasc Res, January 1, 2009; 81(1): 20 - 27. [Abstract] [Full Text] [PDF]