Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2's inhibition of apoptotic calcium signals.
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.
Rong
Yi-Ping
YP
Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Aromolaran
Ademuyiwa S
AS
Bultynck
Geert
G
Zhong
Fei
F
Li
Xiang
X
McColl
Karen
K
Matsuyama
Shigemi
S
Herlitze
Stephan
S
Roderick
H Llewelyn
HL
Bootman
Martin D
MD
Mignery
Gregory A
GA
Parys
Jan B
JB
De Smedt
Humbert
H
Distelhorst
Clark W
CW
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000378:metabolism; D019556:COS Cells; D020013:Calcium Signaling / Q000187:drug effects; D002522:Chlorocebus aethiops; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
D017252:CD3 Complex; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell