期刊
MOLECULAR CELL
卷 31, 期 2, 页码 255-265出版社
CELL PRESS
DOI: 10.1016/j.molcel.2008.06.014
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资金
- BBSRC [BBS/E/B/0000H110] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C116, BBS/E/B/00001116] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C116, BBS/E/B/0000H110, BBS/E/B/00001116] Funding Source: Medline
- NCI NIH HHS [CA42755, R01 CA042755, CA085804, R01 CA085804] Funding Source: Medline
- NHLBI NIH HHS [HL80101, P01 HL080101-040003, P01 HL080101] Funding Source: Medline
- NIMH NIH HHS [MH53367, R29 MH053367, R01 MH053367-10, R01 MH053367] Funding Source: Medline
The antiapoptotic protein Bcl-2 inhibits Ca2+ release from the endoplasmic reticulum (ER). One proposed mechanism involves an interaction of Bcl-2 with the inositol 1,4,5-trisphosphate receptor (IP3R) Ca2+ channel localized with Bcl-2 on the ER. Here we document Bcl-2-IP3R interaction within cells by FRET and identify a Bcl-2 interacting region in the regulatory and coupling domain of the IP3R. A peptide based on this IP3R sequence displaced Bcl-2 from the IP3R and reversed Bcl-2-mediated inhibition of IP3R channel activity in vitro, IP3-induced ER Ca2+ release in permeabilized cells, and cell-permeable IP3 ester-induced Ca2+ elevation in intact cells. This peptide also reversed Bcl-2's inhibition of T cell receptor-induced Ca2+ elevation and apoptosis. Thus, the interaction of Bcl-2 with IP3Rs contributes to the regulation of proapoptotic Ca2+ signals by Bcl-2, suggesting the Bcl-2-IP3R interaction as a potential therapeutic target in diseases associated with Bcl-2's inhibition of cell death.
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