Bax inhibitor-1 is a pH-dependent regulator of Ca2+ channel activity in the endoplasmic reticulum

Hyung Ryong Kim, Geum Hwa Lee, Ki Chan Ha, Taeho Ahn, Ji Yong Moon, Bong Jin Lee, Ssang Goo Cho, Sanguk Kim, Young Rok Seo, Yong Joo Shin, Soo Wan Chae, John C. Reed, Han Jung Chae

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

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 (CΔ-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 CΔ-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.

Original languageEnglish
Pages (from-to)15946-15955
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number23
DOIs
StatePublished - 6 Jun 2008

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